DE3879650T2 - N-ACYL-N-NAPHTHOYLGLYCINE AS ALDOSE REDUCTASE INHIBITORS. - Google Patents

Abstract

Disclosed herein are N-acyl-N-naphthoylglycines, methods for their preparation and intermediates used therein. The N-acyl-N-naphthoylglycines are novel aldose reductase inhibitors useful for the treatment or prevention of diabetic complications and have the formula: <CHEM> wherein R<1> is fluorine, chlorine, bromine or trifluoroethoxy; R<2> is lower alkyl containing 1 to 3 carbon atoms; X is -OH or -NH2 and the pharmaceutically acceptable salts thereof wherein X is -OH.

Description

This invention relates to N-acyl-N-naphthoylglycines, to processes for their preparation, to methods of using the compounds and to pharmaceutical preparations thereof. The compounds have pharmaceutical properties which make them useful for the treatment of diabetes mellitus and related conditions.

For many years, diabetes mellitus has been treated with two established types of drugs, namely insulin and oral hypoglycemic agents. These drugs have benefited hundreds of thousands of diabetics by improving their well-being and prolonging their lives. However, the resulting longevity of diabetics has led to complications such as neuropathy, nephropathy, retinopathy, cataracts and atherosclerosis. These complications have been associated with the undesirable accumulation of sorbitol in diabetic tissues, which in turn resulted from the diabetic's high glucose levels.

In mammals, including humans, the key enzyme involved in the conversion of hexoses to polyols (e.g., the sorbitol pathway) is aldose reductase. J.H. Kinoshita and coworkers, see J.H. Kinoshita et al., Biochem.Biophys.Acta, 158, 472 (1968), and the literature cited therein have shown that aldose reductase plays a central role in the etiology of galactosemic cataracts by causing the conversion of galactose to dulcitol (galactitol), and that an agent capable of inhibiting aldose reductase can prevent the deleterious accumulation of dulcitol in the lens. Furthermore, a relationship between elevated glucose levels and an undesirable accumulation of sorbitol in the lenses, peripheral nerve cord and kidneys of diabetic subjects has been demonstrated, see A. Pirie and R. van Heyningen, Exp.Eye Res., 3, 124 (1964); L.T. Chylack and J.H. Kinoshita, Invest.Ophthal., 8, 401 (1969), and J.D. Ward and R.W.R. Baker, Diabetol., 6, 531 (1970).

The closest prior art is K. Sestanj et al., US Patent 4,568,693, 1986 (Example 52), and US Patent 4,439,617, 1984 (Example 60). K. Sestanj et al. disclose N-naphthoylglycine derivatives with aldose reductase activity. The compounds of the present invention differ in that when they contain a 2-substituent on the naphthalene ring and the N-methyl group is replaced by an acyl group. Still other related compounds with similar utility are N-naphthoylglycine derivatives of Bellini et al., U.S. Patent 4,672,058, 1987, and Sestanj et al., U.S. Patent 4,672,059, 1987; N-(naphthalenylthioxomethyl)amino acid derivatives of K. Sestanj et al., U.S. Patent 4,391,816, 1983; N-[(2-naphthalenyl)thioxomethyl]glycine derivatives of K. Sestanj, U.S. Patent 4,447,452, 1984; and N-[[6-(lower alkoxy)-5-(trifluoromethylthio)-1-naphthalenyl]-thioxomethyl]-N-(lower alkyl)-glycine by F. Bellini et al., US Patent 4,391,825, 1983. Accordingly, the present compounds represent an important new possibility for the treatment of diabetes mellitus.

Y. Mitin et al., Izv. Akad. Nauk SSSR, Ser.Khim. 11, 2666 (1968) (C.A. 70:68721m), disclose N,N-dibenzoylglycine as a chemical intermediate without disclosing any biological activity.

A.J. Bates et al., Helv.Chim.Acta, 58 (3), 688 (1975), disclose N,N'-bis-(benzyloxycarbonyl)-glycylglycine as a chemical intermediate without disclosing any biological activity.

The N-acyl-N-naphthoylglycines of this invention are represented by the formula (I)

wherein R¹ is fluorine, chlorine, bromine or 2,2,2-trifluoroethoxy; R² is lower alkyl having 1 to 3 carbon atoms and X is -OH or -NH₂, and the pharmaceutically acceptable salts thereof, wherein X is -OH.

Preferred compounds of the present invention are represented by formula (1) wherein R¹ is fluorine, chlorine or bromine, R² is methyl or ethyl and X is -OH or -NH₂, and the pharmaceutically acceptable salts thereof, wherein X is -OH.

The most preferred compounds of the present invention are:

N-[[2-fluoro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]- carbonyl]-N-(methoxycarbonyl)-glycine;

[[[2-Fluoro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]- carbonyl]-(methoxycarbonyl)-amino]-acetamide;

N-(ethoxycarbonyl)-N-[[2-fluoro-6-methoxy-5-(trifluoromethyl)- 1-naphthalenyl]-carbonyl]-glycine;

N-[[2-chloro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]- carbonyl]-N-(methoxycarbonyl)-glycine;

N-[[2-Bromo-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]- carbonyl]-N-(methoxycarbonyl)-glycine

and the pharmaceutically acceptable salts thereof.

In addition, the present invention also includes the chemical intermediates of formula (II)

wherein R¹ is as defined above, and chemical intermediates of the formula (VI)

wherein R¹ and R² are as defined above and R³ is tert-butyl or benzyl.

The N-acyl-N-naphthoylglycines of the present invention can be prepared by the processes described below.

There is provided a method of preventing or alleviating complications associated with diabetes mellitus in a diabetic mammal by administering to the mammal a prophylactic or palliative amount of a compound of formula (I). Such complications are neuropathy, nephropathy, retinopathy and cataracts.

The compounds of formula (I) in admixture with a pharmaceutically acceptable carrier form a pharmaceutical composition which can be used according to the above method.

The compounds of this invention represented by formula (I) can exist in rotameric forms. More explicitly, mesomericity imparts partial double bond character to the carbonyl nitrogen bonds. This partial double bond character results in restricted rotation about the carbonyl nitrogen bonds, resulting in cis and trans rotamers, with the restricted rotation being increased by the size of the adjacent groups. The rotameric forms represented by structural formulas (I¹), (I²), (I³) and (I⁴) fall within the scope of this invention:

where R¹, R² and X are as defined above.

For brevity, the compounds of this invention, including their rotameric forms, are referred to as compounds of formula (I).

The compounds of formula (I) wherein X is -OH form salts with suitable therapeutically acceptable inorganic and organic bases. These derived salts have the same potency as their parent acid and are within the scope of this invention. The acid is converted to the corresponding therapeutically acceptable salt in excellent yield by neutralization with the appropriate inorganic or organic base. The salts are usually administered in the same manner as the parent acid compounds. Suitable inorganic bases for forming these salts include the hydroxides, carbonates or bicarbonates of the therapeutically acceptable alkali metals or alkaline earth metals, e.g. sodium, potassium, magnesium, calcium and the like. Suitable organic bases include the following amines: benzylamine; lower mono-, di- and trialkylamines whose alkyl groups contain up to 3 carbon atoms, such as methylamine, dimethylamine, trimethylamine, ethylamine, di- and triethylamine, methylethylamine and the like; mono-, di- and trialkanolamines whose alkanol groups contain up to 3 carbon atoms, e.g. mono-, di- and triethanolamine; alkylenediamines with up to 6 carbon atoms, such as hexamethylenediamine; cyclic saturated or unsaturated bases with up to 6 carbon atoms, such as pyrrolidine, piperidine, morpholine, piperazine and their N-alkyl and N-hydroxyalkyl derivatives, such as N-methylmorpholine and N-(2-hydroxyethyl)piperidine, as well as pyridine. In addition, the corresponding quaternary salts, such as the tetraalkyl (e.g. tetramethyl), alkylalkanol (e.g. methyltriethanol and trimethylmonoethanol) and cyclic ammonium salts, e.g. the N-methylpyridinium, N-methyl-N-(2-hydroxyethyl)-morpholinium, N,N-dimethylmorpholinium, N-methyl-N-(2-hydroxyethyl)-morpholinium and N,N-dimethylpiperidinium salts, can be mentioned, which are characterized by good water solubility. In principle, however, all ammonium salts that are physiologically acceptable can be used.

The conversion into salts can be carried out by a number of known methods. For example, in In the case of inorganic salts, it is preferred to dissolve the acid of formula (I) in water containing at least an equivalent amount of a hydroxide, carbonate or bicarbonate corresponding to the desired inorganic salt. Advantageously, the reaction is carried out in a water-miscible inert organic solvent, e.g. methanol, ethanol, dioxane and the like, in the presence of water. For example, such use of sodium hydroxide, sodium carbonate or sodium bicarbonate gives a solution of the sodium salt. Evaporation of the solution or addition of a water-miscible solvent of more moderate polarity, for example a lower alkanol, e.g. butanol, or a lower alkanone, e.g. ethyl methyl ketone, gives the solid inorganic salt if this form is desired.

To prepare an amine salt, the acidic compound of formula (I) is dissolved in a suitable solvent of either moderate or low polarity, e.g. ethanol, methanol, ethyl acetate, diethyl ether and benzene. Then at least an equivalent amount of the amine corresponding to the desired cation is added to this solution. If the resulting salt does not precipitate, it can usually be obtained in solid form by adding a miscible diluent of lower polarity, e.g. benzene or petroleum ether, or by evaporation. If the amine is relatively volatile, any excess can be easily evaporated off. It is preferred to use substantially equivalent amounts of the less volatile amines.

Salts wherein the cation is quaternary ammonium can be prepared by mixing the acid of formula (I) with an equivalent amount of the corresponding quaternary ammonium hydroxide in water solution, followed by evaporation of the water.

The N-acyl-N-naphthoylglycines of this invention can be administered to mammals, e.g. humans, monkeys or dogs, either alone or in dosage forms, i.e. capsules or tablets, combined with pharmacologically acceptable excipients.

Advantageously, the compounds of this invention may be administered orally. However, the method of administering the present active ingredients of this invention is not intended to be be interpreted as being limited to a particular mode of administration. For example, the compounds may be administered topically in the form of drops of sterile, buffered ophthalmic solutions, preferably of pH 7.2 to 7.6, directly to the eye. They may also be administered orally in solid form containing such excipients as starch, lactose, certain clays, and the like. They may also be administered orally in the form of solutions or injected parenterally. For parenteral administration, they may be used in the form of a sterile solution, preferably of pH 7.2 to 7.6, containing a pharmaceutically acceptable buffer.

The dosage of the N-acyl-N-naphthoylglycines varies with the mode of administration. It also varies with the particular patient being treated. Generally, treatment is initiated with small dosages that are substantially lower than the optimal dose of the compound. In general, the compounds of this invention are most conveniently administered at a concentration level that generally produces effective results without producing any harmful or adverse side effects. For topical administration, a 0.05 to 1.8% solution can be administered dropwise to the eye. The frequency of instillation varies with the patient being treated from one drop every two or three days to once daily. For oral or parenteral administration, the preferred dosage level is about 0.5 to about 1000 mg per kg of body weight per day, although it can be varied as mentioned above. However, a dosage level in the range of about 5.0 to about 60 mg per kg body weight per day is most satisfactory.

Unit dosage forms such as capsules, tablets, pills, and the like can contain from about 25 to about 1250 mg of the active ingredients of this invention with a pharmaceutical carrier. Thus, for oral administration, capsules can contain from about 25 to about 1250 mg of the active ingredients of this invention with or without a pharmaceutical diluent. Effervescent or non-effervescent tablets can contain from about 25 to 1250 mg of the active ingredients of this invention together with conventional pharmaceutical carriers. Thus, tablets, which can be coated and are effervescent or non-effervescent, can be based on known Inert diluents or carriers, for example magnesium carbonate or lactose, may be used together with conventional disintegrating agents, for example magnesium stearate.

The N-acyl-N-naphthoylglycines can also be used in combination with insulin or oral hypoglycemic agents to achieve a beneficial effect in the treatment of diabetes mellitus. In this case, commercially available insulin preparations or oral hypoglycemic agents, e.g. acetohexamide, chlorpropamide, tolazamide, tolbutamide and phenformin, are suitable. The compositions can be administered sequentially or simultaneously with insulin or the oral hypoglycemic agent. Suitable methods of administration, compositions and doses of the insulin preparation or the oral hypoglycemic agent are described in medical textbooks, e.g. "Physicians' Desk Reference", 36th ed., Medical Economics Co., Oradell, J.J., U.S.A., 1982. When used in combination, the N-acyl-N-naphthoylglycines are administered as described above. The N-acyl-N-naphthoylglycines may be administered with the oral hypoglycemic agent in the form of a pharmaceutical composition containing effective amounts of each agent.

The aldose reductase inhibitory activities of the compounds of formula (I) were tested using an in vitro test method similar to that described by S. Hayman and J.H. Kinoshita, J.Biol.Chem., 240, 877 (1965). In the present case, the method of Hayman and Kinoshita was modified by omitting the final chromatography step in the preparation of the enzyme from bovine lentils. The results are shown in Table I under the heading "in vitro".

The aldose reductase inhibiting property of the compounds of this invention and the use of the compounds in preventing, reducing and alleviating diabetic complications by lowering polyol accumulation were also demonstrable in experiments using galactosemic rats, see Dvornik et al., Science, 182, 1146 (1973). Such experiments are exemplified below following the following general commentary concerning these experiments.

(a) Four or more groups of six male rats, 50 to 70 g, Sprague-Dawley strain, were used. The first group, the control group, was fed a mixture of laboratory chow (Rodent Laboratory Chow, Purina) and glucose at 20% (w/w%). The untreated galactosemic group and drug-treated groups were fed similar diets in which glucose was replaced by galactose. The test compound was either mixed into the diet or administered by gavage. In experiments in which the compound was administered in the diet, the mean dose administered was calculated from the actual food intake of the animals in each group. The galactose concentration in the diet of the treated groups was equal to that for the untreated galactosemic group.

(b) After four days, animals were killed by decapitation. The eyeballs were removed and scored with a razor blade; the released lenses were rolled lightly on filter paper and weighed. The sciatic nerves were dissected as completely as possible and weighed. Both tissues can be stored as frozen for up to two weeks before being analyzed for galactite.

(c) Polyol determination was carried out by modifying the method of M. Kraml and L. Cosyns, Clin.Biochem., 2, 373 (1969). Only two minor reagent changes were made: (a) the rinse mixture was an aqueous 5% (w/v) trichloroacetic acid solution and (b) the stock solution was prepared by dissolving 25 mg of dulcitol in 100 ml of aqueous trichloroacetic acid solution. [N.B.: For each experiment, the mean value found in the tissue of glucose-fed rats was subtracted from the individual values found in the corresponding tissue of galactose-fed rats to determine the amount of polyol accumulated.]

A second in vivo model examined the effect of the compounds of the present invention on sorbitol accumulation in the tissues of rats diabeticized for 14 days with streptozocin (STZ) (Upjohn).

In each of the studies, male Sprague-Dawley rats from Charles River Labs., Kingston, NY, weighing 200 to 250 g were used. The animals were weighed and observed before the start of the study.

In each study, rats were randomly assigned by weight to groups of 15 animals, except for group I, which contained 8 animals. The groups were treated as follows:

Group I: Control

Group II: STZ, 110 mg/kg i.p.

Group III: STZ, 110 mg/kg i.p., followed by the reference compound tolrestat, 6 mg/day, given daily by nasogastric tube for 14 days, beginning on the day of induction of diabetes.

Group IV: STZ, 110 mg/kg i.p., followed by varying doses of a compound of the present invention given by nasogastric tube for 14 days starting on the day of induction of diabetes.

After overnight fasting (water ad lib.), animals in groups II to IV were given 110 mg STZ per kg body weight by i.p. injection. The STZ was dissolved in cold citric acid, 0.03 M, pH 4.5, and injected within 5 min after dissolution. Control rats (group I) were injected with buffer only. One hour after injection, standard laboratory chow (Rodent Lab Chow 5001, Purina) was added to the cages.

Two days after STZ injection, plasma glucose levels (from the tail vein) were determined after 4 hours of fasting. Animals with plasma glucose below 300 mg/dl were excluded from the study. Control animals with plasma glucose levels of more than 200 mg/dl were also excluded.

On the morning of day 14 after STZ injection, animals were fasted for 4 hours before sacrifice by decapitation. Blood was collected in heparin-containing tubes and placed on ice. Both lenses and sciatic nerves were immediately removed, weighed, frozen and stored at -20ºC until analysis for sorbitol. RBCs were collected by centrifugation, plasma was removed and cells were washed once with 10 volumes of cold physiological saline. The washed packed RBCs were divided into 1 ml aliquots and extracted with cold perchloric acid and the acid extracts were stored at -20ºC until analysis for sorbitol.

The results shown in Table I show that the N- Acyl-N-naphthoylglycines of this invention exhibit the property of reducing the accumulation of galactite in the lens and sciatic nerve of galactose fed rats. The numbers under L, N and D represent the percent reduction in galactite accumulation in the lens, sciatic nerve and membrane tissues, respectively, for treated rats compared to untreated rats.

Examination of the results presented in Table I below shows that the N-acyl-N-naphthoylglycines of this invention are well suited as aldose reductase inhibitors and that they reduce polyol accumulation in tissues of diabetic or galactosemic rats. For example, N-[[2-fluoro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]-carbonyl]-N-(methoxycarbonyl)-glycine at a dose of 10 mg/kg/day gives comparable results to N-[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]-thioxomethyl]-N-methylglycine at 9 mg/kg/day in the sciatic nerve. The latter compound is also known as tolrestat. TABLE I Example % Inhibition in vitro % Reduction of dulcitol accumulation in vivo TABLE II Example % Inhibition in vitro % Reduction of dulcitol accumulation in vivo (Tolrestat) NS = not significant ND = not determined L = lens N = nerve D = membrane 2 weeks with streptozocin diabetic rat model Treatment mg/kg % Reduction of polyol accumulation in the sciatic nerve Sorbitol (%) Fructose (%) Tolrestat

This invention provides processes for preparing the compounds of formula (I) and the novel intermediates. Accordingly, this invention provides a process for preparing a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof, wherein X is OH, which comprises:

(a) the selective removal of the protecting group R³ from a compound of the formula

wherein R¹ and R² are as defined above and R³ is tert-butyl or benzyl, to give a compound of formula (I) wherein X is OH or

(b) reacting a compound of formula (I) as defined above wherein X is OH with ammonia to obtain a compound of formula (I) where X is NH₂; or

(c) converting a compound of formula (I) as defined above, wherein X is OH, into a pharmaceutically acceptable salt thereof by reaction with a base or converting a pharmaceutically acceptable salt of a compound of Formula (I), into the acid of formula (I) by acid formation.

The N-acyl-N-naphthoylglycines of this invention are illustrated by the following reaction schemes: Scheme I

wherein R¹ and R² are as defined above and R³ is tert-butyl or benzyl. Scheme II Oxidation Scheme III Reduction

Regarding Scheme I, the carboxylic acid (II) is converted to the corresponding carboxylic acid chloride by reacting it with 1 to 5 equivalents of thionyl chloride in a solvent such as dichloromethane, acetonitrile, chloroform, benzene or toluene, or thionyl chloride can be used as solvent. A catalytic amount of dimethylformamide (0.01 to 0.03 eq.) is used. A reaction temperature of 20 to 110 °C is used for reaction times of 10 minutes to 3 hours. Other reagents that can be used under similar conditions are phosphorus trichloride and oxalyl chloride.

The carboxylic acid chloride is prepared by reacting a solution of the acid chloride in an inert organic solvent such as THF, dichloromethane, benzene or toluene with concentrated aqueous Ammonium hydroxide is converted into the corresponding carboxamide (IV) at temperatures from 0 to 25ºC during reaction times from 5 minutes to 1 hour.

The corresponding carboxylic acid amide (IV) can, on the other hand, be formed by reacting the acid chloride with a saturated solution of ammonia gas in an inert solvent (such as THF) at temperatures of 0 to 25ºC for reaction times of 5 minutes to 1 hour.

By reacting (IV) with a base (sodium hydride, potassium hydride, lithium diisopropylamide, 1.0 to 1.5 eq.) in anhydrous THF at temperatures of 0 to 30°C for 20 minutes to 1 hour and then reacting with an alkyl chloroformate (1.0 to 1.2 eq.) at temperatures of 20 to 65°C for 1 to 4 hours, the compound (V) in which R² is Me or Et is formed. When the acid (II) was reacted with ethoxycarbonyl-tert-butylcarbodiimide (1.0 to 1.5 eq.) according to the method of O. Mitsunobu et al., Bull.Chem.Soc., Japan, 45, 3607 (1972), the product was (V) in which R² is Et. The reaction was carried out in an inert solvent such as THF at temperatures from 40 to 80°C for 1 to 10 hours.

On the other hand, when the acid chloride of (II) (prepared as indicated above) is reacted with silver cyanate (1 to 2 eq.) according to the method of CL Arus et al., J.Chem.Soc., 4018 (1954) and 1091 (1957), the product (V) is obtained. The reaction may conveniently be carried out in an inert organic solvent such as carbon tetrachloride, chloroform, dichloromethane or benzene at temperatures of 60 to 100°C for reaction times of 1 to 24 hours. The non-isolated isocyanate intermediate of the formula

This isocyanate is reacted with the appropriate alcohol (1 to 5 eq.) at temperatures of 40 to 90ºC for times of 1 to 3 hours, whereby the compounds (V) in which R² lower alkyl can be obtained.

By reacting (V) in THF or DMF with 1.0 to 1.3 eq. of a base such as sodium hydride, potassium hydride and lithium diisopropylamide (in THF) at temperatures of 0 to 60ºC for 10 minutes to 4 hours and then reacting with tert.butyl bromoacetate or tert.butyl chloroacetate (1.0 to 2.0 eq.) at temperatures of 0 to 65ºC for a period of 30 minutes to 3 days, the compounds (VI) are formed.

The carboxylic acid (II) is converted into a carboxyl-activated form, such as the acid chloride (mentioned above) or the 1-benzotriazolyl ester. A description of the carboxyl-activating groups can be found in general textbooks of peptide chemistry; e.g. K.D. Kopple, "Peptides and Amino Acids", W.A. Benjamin, Inc., New York, 1966, pages 45-51, and E. Schröder and K. Lübke, "The Peptides", vol. 1, Academic Press, New York, 1965, pages 77-128. Examples of the activated form of the terminal carboxyl are the acid chloride, acid bromide, anhydride, azide, the activated ester or O-acylurea obtained from a dialkylcarbodiimide. Preferred activated forms of the carboxyl are the acid chloride, the 1-benzotriazolyl, 2,4,5-trichlorophenyl or succinimido activated ester.

The carboxyl-activated form of formula (II) is then reacted with 1 to 3 molar equivalents of the glycine ester hydrochloride and with 1 to 5 equivalents of triethylamine to give the product of formula (III). The reaction is conveniently carried out in an anhydrous solvent such as tetrahydrofuran or dimethylformamide at temperatures of 15 to 40°C for times of 2 to 24 hours.

By reacting (III) in THF with 1 to 3 equivalents of a base such as sodium hydride, potassium hydride or lithium diisopropylamide at temperatures of 0 and 60°C for 10 minutes to 4 hours and then reacting with an alkyl chloroformate such as methyl or ethyl chloroformate (1 to 2 eq.) at 0 to 45°C for a period of 10 minutes to 24 hours, the compounds (VI) were formed.

On the other hand, a base such as solid sodium hydroxide or solid potassium hydroxide (1.0 to 2.0 eq.) is added to an acetone solution of (III) at -40ºC and stirred for 30 minutes to 1 hour. For this purpose, an alkyl chloroformate such as methyl chloroformate or ethyl chloroformate (1.0 to 2.0 eq.) is added and the reaction temperature is maintained at 20 to 30 °C for 1 to 4 hours to form the compounds (VI).

An alkoxycarbonylglycine ester, such as methoxycarbonylglycine tert.butyl ester, can be reacted with a base, such as sodium or potassium hydride (1 to 1.5 eq.), in an inert solvent, such as THF, to give the corresponding anion of formula (XIII)

[R²OCO CH₂CO₂R³] (XIII),

wherein R² and R³ are as defined above.

The anion (XIII) (1 to 2 eq.) can then be reacted with the acid chloride of the acid (II) in an inert solvent such as THF at temperatures of 0 to 40ºC and for times of 5 minutes to 5 hours.

With regard to process (a) for converting compounds of formula (VI) wherein R³ is tert-butyl into compounds of formula (I) wherein X is -OH, the reaction is conveniently carried out with an organic protic acid such as trifluoroacetic acid (1 eq. to use as solvent) or formic acid (5 eq. to use as solvent) or the reaction may be carried out in a halogenocarbon solvent such as dichloromethane, chloroform or carbon tetrachloride at temperatures of, for example, 20 to 40°C for 1 to 3 hours to give the compounds (I) wherein X is -OH.

Trimethylsilyl iodide, for example (1 to 10 eq.) in a halogenocarbon solvent at temperatures of 20 to 40°C for 1 to 3 hours, can also be used to remove the protecting group and form the compounds (I) in which X is -OH.

When R³ of compound (VI) is CH₂Ph, process (a) can be carried out using catalytic hydrogenation, for example, at 14 to 60 psi H₂ pressure and ambient temperature for 10 minutes to 4 hours using 10% palladium on carbon as catalyst (5 to 20 wt%).

What process (b) for the conversion of compounds of formula (I) wherein X is -OH into compounds of formula (I), wherein X is -NH₂, the compound of formula (I) wherein X is -NH₂ is converted to the acid chloride using the procedures discussed for the formation of the acid chloride of (II). The acid chloride of (I) is then reacted with ammonia, for example ammonia gas dissolved in an inert solvent such as THF or ether, at temperatures of from 0 to 30°C for from 1 to 30 minutes to form the compound (I) wherein X is -NH₂.

Referring to Scheme (II), the compound of formula (VII) is converted into the compound of formula (VIII) by reacting N-bromosuccinimide (1 to 3 eq.) with catalytic benzoyl peroxide (0.001 to 0.1 eq.) in an inert solvent such as carbon tetrachloride at temperatures of 60 to 100°C for 30 minutes to 40 hours.

The conversion of compound (VIII) into compound (IX) is carried out by reacting (VIII) with sodium formate (1 to 10 eq.) in an aqueous alcoholic solvent at 50 to 100 °C for 30 minutes to 4 hours, followed by work-up with an aqueous base (i.e. sodium or potassium hydroxide).

Other hydrolysis conditions, such as sodium carbonate in aqueous alcohol, may be used.

For the conversion of (IX) into (II) where R¹ is -F, -Cl or -Br, excess chromium trioxide in sulphuric acid-water (a mixture known as Jones reagent) in acetone at temperatures from 0 to 30ºC for 30 minutes to 4 hours was used.

On the other hand, excess potassium permanganate could be used as an oxidizing agent in aqueous tert-butyl alcohol at 70 to 100ºC for 30 minutes to 2 hours or in a two-phase mixture of toluene and water with catalytic amounts of tetra-N-butylammonium halide or 18-crown-6-polyether at temperatures of 20 to 100ºC for a period of 1 hour to 4 days.

For the conversion of the compound (II) wherein R¹ is -Br into the compound (II) wherein R¹ is -OCH₂CF₃, the compound (II) wherein R¹ is -Br was treated with sodium trifluoroethoxide formed by reacting trifluoroethanol with an equivalent amount of sodium hydride. On the other hand, Sodium metal, potassium hydride or potassium tert-butoxide could be used to form the metal trifluoroethoxide.

This metal trifluoroethoxide (1 to 15 eq.) was reacted with the bromo acid compound (II) wherein R is -Br in the presence of copper(I) such as cupric iodide (1 to 15 eq.). The reaction was conveniently carried out in THF as solvent or in a polar aprotic solvent such as HMPA or DMF at temperatures of 40 to 120°C for 30 minutes to 6 hours.

Regarding Scheme (III), the compound (X) is converted into the compound (VII) wherein R is -Br by reacting with bromine (1 to 2 eq.) in a solvent such as acetic acid or carbon tetrachloride at 0 to 40°C for a period of 1 to 30 hours.

The conversion of compounds of formula (VII) wherein R is -Br into compounds of formula (VII) wherein R is -Cl is carried out by reacting the compound (VII) wherein R is -Br with copper(I) chloride (1 to 10 eq.) in an inert polar aprotic solvent such as DMSO, DMF or HMPA at temperatures of 150 to 250°C.

The compound (X) was converted into the compound (XI) by reacting the compound (X) with fuming nitric acid (90% S.G. = 1.5, 1 to 10 equivalents) in acetic anhydride at temperatures of -20 to 25ºC for a period of 1 to 3 hours.

Other reagents that may be used are concentrated nitric acid (70%) at temperatures from 0 to 30ºC and for periods from 30 minutes to 1 ½ hours, nitric acid in acetic acid at 25ºC, sodium nitrate in trifluoroacetic acid at 0ºC and ammonium nitrate in trifluoroacetic anhydride at 25ºC.

The reduction of the compound (XI) to (XII) is carried out by catalytic amounts of 10% palladium on carbon (5 to 20 wt.%) in an alcoholic solvent or ethyl acetate at room temperature at 20 to 60 psi H₂ pressure. Alternatively, zinc in acid, iron powder or stannous chloride in acid can be used.

The conversion of the compound (XII) into the compound (VII) in which R¹ is -F is carried out with sodium nitrite (1 to 3 eq.) in hydrogen fluoride-pyridine at temperatures of -78 to 65ºC for periods of 30 minutes to 4 hours.

On the other hand, reaction of the amine (XII) with sodium nitrite (1 to 3 eq.) in aqueous tetrafluoroboric acid at 0 to 30°C for 20 minutes to 1 hour gives the corresponding diazonium tetrafluoroborate (VII) in which R¹ is N₂BF₄, which is then pyrolyzed neat or in an inert solvent such as xylenes or chlorobenzene at temperatures of 100 to 200°C for periods of 10 minutes to 1 hour.

The following examples further illustrate this invention.

Example 1: N-[[2-Fluoro-6-methoxy-5-(trifluoromethyl)-1- naphthalenyl]-carbonyl]-N-(methoxycarbonyl)-glycine (I): R¹ = -F; R² = -CH₃; X = -OH Step 1) Preparation of the 1,1-dimethylethyl ester of N-[[2- Fluoro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]-carbonyl]- glycine

A solution of 17.0 g (59.0 mmol) of 2-fluoro-6-methoxy-5- (trifluoromethyl)-1-naphthoic acid (prepared by the procedure of Example 10), 11.96 g (1.5 eq.) of 1-hydroxybenzotriazole and 13.57 g (1.2 eq.) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 375 mL of dry DMF was stirred at room temperature under dry N2 atmosphere for 1 1/4 h. 19.78 g (2.0 eq.) of glycine tert-butyl ester hydrochloride and 27.1 mL (3.3 eq.) of triethylamine were added and the resulting suspension was stirred for 30 min. The reaction mixture was poured into 3 L of water and extracted three times with 300 mL of ether each time. The combined ether extracts were concentrated and the solid product was washed well with water and dried in vacuo to give 21.98 g (93%) of the title compound as a white solid. A small amount was flash chromatographed for analysis (99:1 CHCl3:CH3CN), mp 144-146 °C.

NMR (CDCl3, 400 MHz): δ 1.50 (s, 9H, OC(C₃)₃), 3.98 (s, 3H, OCH₃), 4.22 (d, 2H, J=5.5Hz, NHC₂), 6 ,50 (m, 1H, N CH₂), 7.35 (m, 2H, Ar ), 8.25 (m, 1H, Ar ), 8.35 (d, 1H, ArH).

IR (CHCl₃, cm⁻¹): 3450, 3430 (NH), 1735 (CO₂tBu), 1665 (CON).

Analysis: Calculated: C 56.86 H 4.77 N 3.49 %

found: C 56.96 H 4.66 N 3.62%.

Step 2) Preparation of the 1,1-dimethylethyl ester of N-[[2- Fluoro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]-carbony1]-N- (methoxycarbonyl)-glycine

1.81 g (1.1 eq.) of sodium hydride (80% dispersion in mineral oil) was added to a stirred solution of 21.98 g (54.76 mmol) of the 1,1-dimethylethyl ester of N-[[2-fluoro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]glycine in 450 mL of dry THF kept at room temperature under a dry N2 atmosphere. The suspension was heated in an oil bath at 50°C until hydrogen evolution ceased (approximately 2 h). The reaction mixture was cooled to 0-5°C and a solution of 5.76 mL (1.36 eq.) of methyl chloroformate in 150 mL of dry THF was added dropwise over 20 min. The reaction mixture was then warmed to room temperature and stirred for 30 min. The reaction mixture was quenched with saturated aqueous NH4Cl and diluted with 500 mL of ether. 100 mL of silica gel was added and the solvents were removed in vacuo. The silica absorbate was flash chromatographed (gradient elution 4:1 to 7:3 petroleum ether:ethyl acetate, silica) to give 18.79 g (75%) of the title compound as a white solid and 3.07 g (14%) of starting material. A small amount was recrystallized from petroleum ether:ether for analysis, mp 111-114 °C.

NMR (CDCl3, 200 MHz): δ 1.54 (s, 9H, OC(C₃)₃), 3.57 (s, 3H, CO₂C₃), 3.99 (s, 3H, OC₃), 4.65 ( m, 2H, NHC₂), 7.35 (m, 2H, ArH), 8.12 (d, 1H, ArH), 8.28 (m, 1H, ArH).

IR (pure, cm-1): 1755, 1740, 1690 (C=O).

Analysis: Calculated: C 54.90 H 4.61 N 3.05 %

Found: C 55.09 H 4.45 N 3.12%. Step 3) Preparation of N-[[2-fluoro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]-N-(methoxycarbonyl)glycine 18.79 g (40.90 mmol) of the 1,1-dimethylethyl ester of N-[[2-fluoro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]-N-(methoxycarbonyl)glycine was suspended in 575 ml of dry formic acid and stirred at room temperature. Dissolution occurred within 15 min. After 1 h the reaction was complete. The reaction mixture was concentrated in vacuo and added to 4 L of water. This aqueous suspension was stirred for 30 min with heating (about 40-50 °C) to ensure appropriate solidification. The resulting solid was collected, washed twice with 150 mL of water and dried in vacuo at 100 °C to give the title compound as a white solid in 94% yield, mp 160-162 °C.

NMR (d6DMSO, 400 MHz): δ 3.53 (s, 3H, CO₂C₃), 4.01 (s, 3H, OC₃), 4.62 (m, 1H, NC ¹H²), 4.71 (m, 1H, NCH¹ ² ), 7.63 (t, 1H, Ar ), 7.72 (d, 1H, ArH), 8.15 (m, 2H, ArH).

IR (KBr, cm-1): 3600-2450 (CO-2H), 1765, 1695 (C=O).

MS (c/e): 403 (48%), 271 (100%).

Analysis: Calculated: C 50.63 H 3.25 N 3.47 %

found: C 50.81 H 3.44 N 3.62%.

Example 2: [[[2-Fluoro-6-methoxy-5-(trifluoromethyl)-1- naphthalenyl]-carbonyl]-(methoxycarbonyl)-amino]-acetamide

(I): R¹ = -F; R² = -CH₃; X = -NH2

6 μl (0.067 eq) of dimethylformamide and 130 μl (1.2 eq) of oxalyl chloride were added to a stirred solution of N-[[2-fluoro-6- methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]-N- (methoxycarbonyl)glycine in 2.5 mL of anhydrous methylene chloride at 0°C under a dry nitrogen atmosphere. After 5 min, the reaction mixture was warmed to room temperature. After 1 3/4 h, the organic materials were removed. The residue was dissolved in 30 mL of anhydrous ether at 0°C and ammonia gas was bubbled in for 1 min. The reaction mixture was immediately quenched with 30 mL of hexane. The solid was collected by suction filtration and suspended in 75 mL of ethyl acetate. The ethyl acetate layer was washed twice with 25 mL of water and dried with magnesium sulfate and the ethyl acetate was removed. The solid was combined with that from another run and recrystallized from chloroform:petroleum ether to give the title compound as a white solid (325 mg, 54% combined yield), m.p. 199-202 °C.

NMR (DMSO-d6, 400 MHz): δ 3.49 (s, 3H CO₂C ₃), 4.00 (s, 3H, ArOC ₃), 4.42 (d, 1H, J=16.4Hz, NC ¹H²CONH₂), 4.66 (d, 1H, J=16.4Hz, NCH¹ ²CONH₂), 7.27 (s, 1H, CON ¹H²), 7.62 (t, 1H, J=9.4Hz, ArH), 7.71 (d, 2H, J=9.8Hz, ArH and CONH¹ ²), 8.11 (m, 1H, ArH), 8.35 (d, 1H, J=9.4Hz, Ar ).

IR (KBr, cm-1): 3420 and 3330 (NH2), 1742 (C=O), 1678 (2C=O), 1615 and 1588 (C=C).

MS (z/e): 402 (M+, 21%), 271 (100%).

Analysis: Calculated: C 50.75 H 3.51 N 6.96 %

found: C 50.94 H 3.78 N 6.86%.

Example 3: N-(ethoxycarbonyl)-N-[[2-fluoro-6-methoxy-5- (trifluoromethyl)-1-naphthalenyl]-carbonyl]-glycine (I): R¹ = -F; R² = -C₂H₅; X = -OH Step 1) Preparation of the ethyl ester of N-[[2-fluoro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]-carbonyl]-carbamic acid

According to the procedure of O.Mitsunobu et al., Bull.Chem.Soc. Japan, 45, 3607 (1972), a solution of 2.30 g (8.00 mmol) of 2-fluoro-6-methoxy-5-(trifluoromethyl)-1-naphthoic acid (prepared by the procedure of Example 10) and 1.50 g (1.1 eq.) of ethoxycarbonyl tert-butylcarbodiimide in 40 mL of anhydrous THF was refluxed under a dry nitrogen atmosphere for 2½ h. The reaction mixture was cooled to room temperature and the THF was removed. The crude product was triturated with ether to give 2.37 g (82%) of the title compound as an almost white solid. A small sample was recrystallized from CHCl3: petroleum ether for analysis, mp 172-174ºC.

NMR (CDCl3, 200 MHz): δ 1.24 (t, 3H, J=6.9Hz, CO₂CH₂C₃), 3.98 (s, 3H, ArOC₃), 4.18 (q, 2H, J=6.8Hz, CO₂C ₂CH₃), 7.34 (m, 2H, 2Ar ), 7.94 (s, 1H, N ), 8.14 (d, 1H, J=9.5Hz, Ar ), 8, 33 (m, 1H, Ar ).

IR (CHCl₃, cm⁻¹): 3400 (NH), 1781 (C=O), 1692 (C=O), 1611 and 1583 (C=O).

Exact mass: Calculated 359.0785; found 359.0780.

Step 2) Preparation of the 1,1-dimethylethyl ester of N-[[2- fluoro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]-carbonyl]-N- (ethoxycarbonyl)-glycine

0.208 g (1.1 eq.) of sodium hydride (80 wt.% dispersion in mineral oil) was added to a stirred solution of 2.26 g (6.29 mmol) of the ethyl ester of N-[[2-fluoro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]carbamic acid in 75 ml of anhydrous tetrahydrofuran at room temperature under a dry nitrogen atmosphere. After 45 min, 1.52 ml (1.5 eq.) of tert-butyl bromoacetate was added and the reaction mixture was heated to 60°C. After 1 ¼ h of heating, the reaction mixture was cooled to room temperature and the THF was removed. The residue was suspended in 150 ml of ether, washed twice with 75 ml of water and once with 50 ml of saturated aqueous NaCl, dried with MgSO4 and the ether removed. The crude oil was flash chromatographed (4:1 petroleum ether:ethyl acetate, silica) and then triturated three times with 30 ml of petroleum ether to give 2.40 g (81%) of the title compound as a white powder, m.p. 81-83°C.

NMR (CDCl3, 200 MHz): δ 0.81 (t, 3H, J=7.4Hz, CO₂CH₂C₃), 1.53 (s, 9H, CO₂C(C₃)₃), 3.98 (m, 5H , ArOC 3 and CO 2 C 2 CH 3 ), 4.65 (broad d, 2H, NC 2 CO 2 ), 7.31 (t, 1H, J=9.5Hz, Ar ), 7.40 (d, 1H, J=9.5Hz, Ar ), 8.14 (d, 1H, J=9.2Hz, Ar ), 8.23 (m, 1H, ArH).

IR (CHCl₃, cm⁻¹): 2990 (CH), 1740 (C=O), 1675 (C=O), 1610 and 1580 (C=C).

Analysis: Calculated: C 55.81 H 4.90 N 2.96 %

Found: C 55.86 H 5.10 N 2.97%.

Step 3) N-(ethoxycarbonyl)-N-[[2-fluoro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]-carbonyl]-glycine

A suspension of 2.40 g (5.07 mmol) of the 1,1-dimethylethyl ester of N-[[2-fluoro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]-N-(ethoxycarbonyl)glycine in 90 ml of formic acid was stirred at room temperature under a dry nitrogen atmosphere. Dissolution occurred after 10 min. After 1 ½ h, the reaction solution was diluted with 1 l of water. The resulting suspension was stirred rapidly for 45 min and then filtered. The solid was washed three times with 20 ml of water each time, air-dried and recrystallized from benzene:petroleum ether to give 1.21 g (57%) of the title compound as white needles, m.p. 135.5-138°C.

NMR (DMSO-d6, 400 MHz): δ 0.71 (t, 3H, J=7.1Hz, CO₂CH₂C₃), 3.88 (q, 2H, J=6.9Hz, CO₂C₂CH₃), 4.01 ( s, 3H, ArOC&sub3;), 4.64 (dd, 2H, J=16.3 and 24.4Hz NC&sub2;CO&sub2;H), 7.64 (t, 1H, J=9.3Hz, ArH) , 7.74 (d, 1H, J=9.5Hz, Ar ), 8.16 (d, 2H, J=9.4Hz, 2Ar ).

IR (KBr, cm-1): 1755 (CO-2H), 1702 (C=O), 1682 (C=O), 1609 and 1572 (C=C).

MS (Cl): 418 (32%), 398 (33%), 323 (75%), 271 (100%).

Analysis: Calculated: C 51.81 H 3.62 N 3.36 %

found: C 51.90 H 3.87 N 3.32%.

Example 4: N-[[2-chloro-6-methoxy-5-(trifluoromethyl)-1- naphthalenyl]-carbonyl]-N-(methoxycarbonyl)-glycine (I): R¹ = -Cl; R² = -CH₃; X = -OH Step 1) Preparation of the 1,1-dimethylethyl ester of N-[[2- chloro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]-carbonyl]- glycine

2.45 g (1.5 eq.) of 1-hydroxybenzotriazole hydrate and 2.78 g (1.2 eq.) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added to a stirred solution of 3.69 g (12.11 mmol) of 2-chloro-6-methoxy-5-(trifluoromethyl)-naphthoic acid (prepared by the procedure of Step 3, Example 12) in 78 mL of dry dimethylformamide. After stirring for 1 ½ h at room temperature, 4.06 g (2 eq.) of glycine tert-butyl ester hydrochloride and 5.8 mL (3.3 eq.) of triethylamine (dried over KOH) were added. After stirring for 3 h, the reaction mixture was diluted with 1 L of water and extracted three times with 350 mL of ether each time. Silica gel was added to the extracts and the solvent was removed. The absorbate was flash chromatographed (70:30 petroleum ether:ethyl acetate) to give 3.95 g (80%) of the title compound as a white solid, m.p. 166-167 °C.

NMR (CDCl3, 200 MHz): δ 1.50 (s, 9H, C(C₃)₃), 3.98 (s, 3H, OC₃), 4.22 (d, 2H, J=4Hz, NC₂), 6, 34 (s, 1H, N ), 7.38 (d, 1H, J=10Hz, Ar ), 7.48 (d, 1H, J=10Hz, Ar ), 8.15 (d, 2H, J=9Hz , Ar ).

IR (CHCl₃, cm⁻¹): 1730 (C=O), 1660 (C=O).

Exact mass: Calculated = 417.09557; found 417.0984.

Step 2) Preparation of the 1,1-dimethylethyl ester of N-[[2-chloro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]-carbonyl]-N(methoxycarbonyl)-glycine

To a suspension of 0.9 g (1.2 eq.) of potassium hydride (35 wt. % dispersion in mineral oil) in 20 ml of dry tetrahydrofuran under argon at room temperature was added dropwise 2.73 g (6.53 mmol) of 1,1-dimethylethyl ester of N-[[2-chloro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]glycine in 30 ml of dry THF. After stirring for 25 min, the reaction mixture was cooled in an ice bath and a solution of 0.7 ml (1.4 eq.) of methyl chloroformate in 18 ml of dry THF was added dropwise over a period of 20 min. After stirring for 1 h, the reaction mixture was quenched with saturated aqueous ammonium chloride and diluted with 300 mL of ether. The ether layer was separated and dried over magnesium sulfate. Silica gel was added and the ether removed. The silica absorbate was flash chromatographed (4:1 petroleum ether:EtOAc) to afford 2.10 g (67%) of the title compound as a white solid. A small sample was further purified by trituration with petroleum ether, m.p. 117-118 °C.

NMR (CDCl3, 200 MHz): δ 1.54 (s, 9H, C(C₃)₃), 3.55 (s, 3H, COOC₃) 3.98 (s, 3H, ArOC₃), 4.48 (d, 1H , J=17Hz, NC ¹H²), 4.85 (d, 1H, J=17Hz, NCH¹ ²), 7.40 (d, 1H, J=10Hz, Ar ), 7.48 (d, 1H, J= 10Hz, Ar ), 8.10 (d, 1H, J=10Hz, Ar ), 8.17 (d, 1H, J=10Hz, ArH).

IR (CHCl₃, cm⁻¹): 1740 (C=O), 1725 (C=O), 1625 (C=O).

Analysis: Calculated: C 53.01 H 4.45 N 2.94 %

found: C 52.89 H 4.40 N 2.63%.

Step 3) Preparation of N-[[2-chloro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]-carbonyl]-N-(methoxycarbonyl)-glycine

1,1-dimethylethyl ester of N-[[2-chloro-6- methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]-N-(methoxycarbonyl)glycine (3.10 g, 6.51 mmol) was suspended in 122 mL of formic acid under nitrogen at room temperature and stirred for 1 1/2 h. The reaction mixture was diluted with 1 1/2 L of water and extracted twice with 200 mL of ether each time. The extracts were combined, dried over magnesium sulfate and concentrated. The residue was recrystallized from benzene to give 1.76 g (64%) of the title compound as a white solid, m.p. 162-165 °C. NMR (d6DMSO, 400 MHz): δ 3.52 (s, 3H, COOC₃), 4.02 (s, 3H, ArOC₃), 4.61 (d, 1H, J=7Hz, NC¹H²), 4.73 (d, 1H, J=7Hz, NCH¹²), 7.70 (d, 1H, J=4Hz, ArH), 7.72 (d, 1H, J=4Hz, Ar), 8.09 (d, 1H, J=10Hz, Ar), 8.12 (d, 1H, J=10Hz, Ar).

IR (KBr, cm-1): 1761 (C=O), 1738 (C=O), 1700 (C=O), 1622 and 1595 (C=C).

MS (c/e): 419 (6%), 385 (21%), 384 (100%), 287 (42%), 132 (30%), 129 (29%).

Analysis: Calculated: C 48.65 H 3.12 N 3.34 %

found: C 48.60 H 2.99 N 3.34%.

Example 5 : N-[[2-Bromo-6-methoxy-5-(trifluoromethyl)-1- naphthalenyl]-carbonyl]-N-(methoxycarbonyl)-glycine (I): R¹ = -Br; R² = -CH₃; X = -OH Step 1) Preparation of 2-bromo-6-methoxy-5-(trifluoromethyl)- 1-naphthalenecarboxamide

A suspension of 2.0 g (5.73 mmol) of 2-bromo-6-methoxy-5-trifluoromethyl-1-naphthoic acid (prepared by the procedure of Example 11, Step 2), 11 mL of thionyl chloride, and 40 µL (0.095 eq.) of dimethylformamide was heated with stirring at 60 °C under a dry N2 atmosphere for 35 min. The reaction mixture was cooled to room temperature and the thionyl chloride was removed. The solid residue was dissolved in 20 mL of THF and this solution was added dropwise to the stirred, cold (0-5 °C) ammonium hydroxide over 5 min. After 15 min, 100 mL of water was added and the suspension was filtered. The solid was washed with water and dried in vacuo to give 1.80 g (90%) of the title compound as a white solid.

NMR (d6DMSO, 200 MHz): δ 3.99 (s, 3H, OC3), 7.88 (m, 2H, Ar), 7.90-8.25 (m, 4H, N2, Ar).

Step 2) Methyl ester of N-[[2-bromo-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]-carbonyl]-carbamic acid

2-Bromo-6-methoxy-5-(trifluoromethyl)-1-naphthalenecarboxamide (4.18 g, 12.01 mmol) was added to a stirred suspension of sodium hydride (50% dispersion in mineral oil) (632 mg, 1.1 eq) in anhydrous THF (110 mL) pre-chilled in an ice bath under a dry N2 atmosphere. The ice bath was removed and the suspension was stirred at ambient temperature for 30 min, warmed to 40 °C and stirred for an additional 20 min. The reaction mixture was cooled to room temperature and methyl chloroformate (0.93 mL, 1.0 eq) in THF (25 mL) was added dropwise over 10 min. After an additional 20 min, 35 mL of saturated aqueous NH4Cl was added. The reaction mixture was added to 400 ml of water and extracted twice with 300 ml of ether each time. The combined ether extracts were washed with 300 ml of saturated aqueous NaCl. 25 ml of silica gel was added to the ether solution and the solvent was removed. The silica absorbate was flash chromatographed (3:2 petroleum ether:ethyl acetate, silica), to give 2.71 g (56%) of the title compound as a white solid, mp 180-182 °C.

NMR (CDCl3, 200 MHz): δ 3.75 (s, 3H, CO₂C₃), 4.01 (s, 3H OC₃) 7.38 (d, 1H, ArH), 7.68 (d, 1H, Ar ), 7, 52 (d, 1H, ArH), 8.17 (d, 1H, ArH).

IR (CHCl₃, cm⁻¹): 3400 (NH), 1770, 1700 (CONCO).

Analysis: Calculated: C 44.36 H 2.73 N 3.45 %

Found: C 44.28 H 2.42 N 3.30%.

Step 3) Preparation of the 1,1-dimethylethyl ester of N-[[2- bromo-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]-carbonyl]-N- (methoxycarbonyl)-glycine

Sodium hydride (2.61 g, 6.43 mmol) was added to a stirred solution of the methyl ester of N-[[2-bromo-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]carbamic acid (2.61 g, 6.43 mmol) in dry THF (95 mL) at room temperature under dry N2 atmosphere. After 1 h, tert-butyl bromoacetate (1.56 mL, 1.5 eq) was added and the reaction mixture was heated to 60°C for 2½ h. The reaction mixture was cooled to room temperature and the THF was removed. Water (100 mL) was added and the resulting solid was filtered. The resulting solid was washed with water and then petroleum ether and dried in vacuo to give the title compound (2.81 g, 84%) as a white solid. A small amount was recrystallized from petroleum ether:ether, mp 126-128ºC.

NMR (CDCl3, 200 MHz): δ 1.54 (s, 9H, C(C₃)₃), 3.54 (s, 3H, CO₂C₃) 3.98 (s, 3H, OC₃), 4.48 (d , 1H, J=17.2Hz, NC ¹H²), 4.86 (d, 1H, J=17.2Hz, NCH¹ ²), 7.38 (d, 1H, ArH), 7.61 (d, 1H, Ar ), 8.09 (m, 2H, Ar ).

IR (CHCl₃, cm⁻¹): 1750, 1690 (C=O).

Analysis: Calculated: C 48.48 H 4.07 N 2.69 %

Found: C 48.61 H 4.37 N 2.60%.

Step 4) Preparation of N-[[2-bromo-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]-carbonyl]-N-(methoxycarbonyl)-glycine

To 2.67 g (5.13 mmol) of 1,1-dimethyl ester of N-[[2-bromo-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]-N-(methoxycarbonyl)glycine was added 100 ml of formic acid and the suspension was stirred at room temperature under a dry N2 atmosphere. Dissolution occurred within 20 min. After 2 h, the reaction mixture was added to 1.2 L of rapidly stirred water. The resulting solid was filtered off and washed well with water. The solid was taken up in 200 mL of ethyl acetate, dried (MgSO₄) and the solvent removed. The resulting oil was triturated with petroleum ether to give 1.84 g (77%) of the title compound as a white solid. This solid was further purified by recrystallization from petroleum ether:chloroform (0.87 g, 37%), m.p. 164-166 °C.

NMR (d6DMSO, 400 MHz): δ 3.52 (s, 3H, CO₂C₃), 4.02 (s, 3H, OC₃), 4.60 (d, 1H, J=17.5Hz, NC ¹H²), 4.74 ( d, 1H, J=17.5Hz, NCH¹ ²), 7.70 (d, 1H, J=9.5Hz, Ar ), 7.81 (d, 1H, J=4.5Hz, Ar ), 8, 01 (dm, 1H, Ar ), 8.14 (d, 1H, J=9.5Hz, ArH).

IR (KBr, cm-1): 3650-2500 (CO-2H), 1770, 1740, 1730, 1695 (C=O).

MS (c/e): 465 (8%), 463 (8%), 384 (100%), 333 (30%), 331 (30 %).

Analysis: Calculated: C 43.99 H 2.82 N 3.02 %

found: C 43.84 H 2.44 N 3.07%.

Example 6: N-[[6-Methoxy-2-(2,2,2-trifluoroethoxy)-5- (trifluoromethyl)-1-naphthalenyl]-carbonyl]-N-(methoxycarbonyl)- glycine (I): R¹ = -O-CH₂-CF₃; R² = -CH₃; X = -OH Step 1) Preparation of the 1,1-dimethylethyl ester of N-[[6- methoxy-2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)-1-naphthalenyl]-carbonyl]-glycine

To a stirred solution of 7.75 g (21.0 mmol) of 6-methoxy-2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)-naphthoic acid (prepared by the method of Example 11, Step 3) in 135 mL of anhydrous dimethylformamide under a dry nitrogen atmosphere at room temperature were added 4.27 g (1.5 eq.) of 1-hydroxybenzotriazole and 4.84 g (1.2 eq.) of 1-(3-dimethylaminopropyl)-3-ethoxycarbodiimide hydrochloride. After 1 1/4 h, 7.06 g (2.0 eq.) of glycine tert-butyl ester hydrochloride and 9.68 mL (3.3 eq.) of anhydrous triethylamine were added. After a further 2 h, the reaction mixture was diluted with 1.5 l of water and extracted four times with 200 ml of ether each time. The extracts were combined and the ether removed. The crude product was flash chromatographed (7:3 petroleum ether:ethyl acetate, silica) to give 7.39 g (73%) of the title compound as a white solid, m.p. 146-147.5 °C.

NMR (CDCl3, 200 MHz): δ 1.50 (s, 9H, CO2C(C3)3), 3.97 (s, 3H, ArOC3), 4.20 (d, 2H, J=5.5Hz, NHCCO2) ), 4.48 (q, 2H, J=8.3Hz, OC 2 CF 3 ), 6.44 (broad t, 1H, J= 5Hz, N CH 2 ), 7.27 (d, 1H, J =9.9Hz, Ar ), 7.37 (d, 1H, J=9.5Hz, Ar ), 8.23 (d, 2H, J=9.2Hz, 2Ar ).

IR (CHCl₃, cm⁻¹): 3440 (NH), 1736 (C=O), 1662 (CON), 1598

Analysis: Calculated: C 52.40 H 4.40 N 2.91 %

Found: C 52.09 H 4.43 N 2.95%.

Step 2) Preparation of the 1,1-dimethylethyl ester of N-[[6- methoxy-2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)-1-naphthalenyl]-carbonyl]-glycine

To a stirred solution of 5.56 g (11.5 mmol) of the 1,1-dimethylethyl ester of N-[[6-methoxy-2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]glycine in 90 mL of anhydrous THF under a dry nitrogen atmosphere at room temperature was added 381 mg (1.1 eq.) of sodium hydride (80 wt. % dispersion in mineral oil). The reaction mixture was heated to 55°C for 2 h and then cooled to 0°C in an ice bath. A solution of 1.21 mL (1.36 eq.) of methyl chloroformate in 30 mL of anhydrous THF was slowly added over 25 min to the reaction mixture cooled to 0°C. After 10 min, the reaction mixture was warmed to room temperature. After 1 h, the reaction mixture was quenched with 1 mL of saturated aqueous ammonium chloride, diluted with 100 mL of ether and preabsorbed onto silica gel. The product was flash chromatographed (4:1 petroleum ether:ethyl acetate, silica) to give 4.42 g (71%) of the title compound as white flakes, m.p. 53-54 °C. NMR (CDCl3, 200 MHz): δ 1.53 (s, 9H, CO2C(C3)3), 3.53 (s, 3H, NCO2C3), 3.97 (s, 3H, ArOC3), 4.43 (m, 3H, ArOC2CF3 and NC1H2CO2), 4.8 (broad d, 2H, J=15Hz, N-CH12CO2), 7.23 (d,1H, J=9.4Hz, Ar), 7.37 (d, 1H, J=9.5Hz, Ar), 8.06 (d, 1H, J=9.6Hz, Ar), 8.26 (d, 1H, J=9.3Hz, Ar).

IR (CHCl₃, cm⁻¹): 1745 (2C=O), 1672 (CON), 1600 (C=C).

Analysis: Calculated: C 51.21 H 4.30 N 2.60 %

found: C 50.94 H 4.97 N 2.52%.

Step 3) Preparation of N-[[6-methoxy-2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)-1-naphthalenyl]-carbonyl]-N- (methoxycarbonyl)-glycine

A suspension of 5.86 g (10.9 mmol) of the 1,1-dimethylethyl ester of N-[[6-methoxy-2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]-N-(methoxycarbonyl)glycine in 135 ml of formic acid was stirred at room temperature under a dry nitrogen atmosphere. Dissolution occurred after 10 min. After 1 h, the reaction mixture was diluted with 1.5 l of water and extracted twice with 400 ml of ether each time. The extracts were combined and the ether removed. The residue was suspended in 100 ml of water and filtered. The solid was washed twice with 20 ml of water each time and air dried. The crude product was recrystallized from chloroform to give 4.15 g (79%) of the title compound as a white powder, m.p. 186-187°C.

NMR (d6DMSO, 400 MHz): δ 3.48 (s, 3H, NCO₂C₃), 3.99 (s, 3H, ArOC₃), 4.51 (d, 1H, J=16.4Hz, NC ¹H²CO₂H), 4, 67 (d, 1H, J=16.9Hz, NCH¹ ²CO₂H), 4.89 (q, 2H, J=7.8Hz, ArOC ₂CF₃), 7.66 (d, 2H, J=9 ,7Hz, Ar ), 7.99 (d, 1H, J=9.5Hz, Ar ), 8.11 (d, 1H, J=9.5Hz, ArH).

IR (KBr, cm-1): 1771 (C=O), 1746 (C=O), 1682 (C=O), 1612 (C=C).

MS (z/e): 483 (M+, 50%), 351 (94%), 274 (27%), 205 (79%), 134 (100%).

Analysis: Calculated: C 47.22 H 3.13 N 2.90 %

Found: C 47.12 H 3.44 N 2.37%.

Example 7: N-(ethoxycarbonyl)-N-[[6-methoxy-2-(2,2,2- trifluoroethoxy)-5-(trifluoromethyl)-1-naphthalenyl]-carbonyl]- glycine (I) R¹ = -O-CH₂-CF₃; R² = -CH₂CH₃, X = -OH. Step 1) Preparation of the ethyl ester of N-[[6-methoxy-2- (2,2,2-trifluoroethoxy)-5-(trifluoromethyl)-1-naphthalenyl]-carbonyl]-carbamic acid

According to the method of O. Mitsunobu et al., Bull.Chem.Soc. Japan, 45, 3607 (1972), a solution of 4.75 g (12.9 mmol) of 6-methoxy-2-(2,2,2-trifluoroethoxy)-5-trifluoromethyl)naphthoic acid and 2.40 g (1.10 eq.) of ethoxycarbonyl-tert-butylcarbodiimide in 65 ml of anhydrous THF was refluxed for 2 h under a dry nitrogen atmosphere. The reaction mixture was then cooled to room temperature and the THF was removed. The resulting solid was triturated twice with 15 ml of ether each time to give 4.71 g (83%) of the title compound as a beige powder. A small sample was recrystallized from chloroform:hexane to give white crystals for analysis, m.p. 158-160 °C.

NMR (CDCl3, 200 MHz): δ 1.21 (t, 3H, J=6.8Hz, CO₂CH₂C₃), 3.97 (s, 3H, ArOC₃), 4.13 (q, 2H, J=6.9Hz, NHCO₃C₂CH₃), 4.48 (q, 2H, J=7.9Hz, OC₂CF₃), 7.25 (d, 1H, J=9.5Hz, Ar ), 7.36 (d, 1H, J=9.5Hz, Ar ), 7.94 (s, 1H, N ), 8.01 (d, 1H, J=9.5Hz, ArH), 8.30 (d, 1H, J=9.9Hz, Ar ).

IR (CHCl₃, cm⁻¹): 3395 (NH), 2970 (CH), 1779 and 1766 (C=O), 1694 (C=O), 1605 (C=C).

Analysis: Calculated: C 49.21 H 3.44 N 3.19 %

found: C 49.47 H 3.11 N 3.29%.

Step 2) Preparation of the 1,1-dimethylethyl ester of N- (ethoxycarbonyl)-N-[[6-methoxy-2-(2,2,2-trifluoroethoxy)-5- (trifluoromethyl)-1-naphthalenyl]-carbonyl]-glycine

To a stirred solution of 4.60 g g (10.5 mmol) of the ethyl ester of N-[[6-methoxy-2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]carbamic acid in 125 mL of anhydrous THF at room temperature under a dry nitrogen atmosphere was added 0.346 g (1.1 eq.) of sodium hydride (80 wt.% dispersion in mineral oil). After 1 h, 2.54 mL (1.5 eq.) of tert-butyl bromoacetate was added. The reaction mixture was heated to 65°C for 1 h, cooled to room temperature and the THF was removed. The residue was dissolved in 200 mL of ether and washed twice with 50 mL of water and once with 50 mL of saturated aqueous NaCl. The ether phase was dried with magnesium sulfate and the ether removed. The crude product was flash chromatographed (17:3 petroleum ether:ethyl acetate, silica) and triturated with petroleum ether to give 4.60 g (79%) of the title compound as a white powder, m.p. 84-86 °C.

NMR (CDCl3, 200 MHz): δ 0.80 (t, 3H, J=7.4Hz, CO₂CH₂C₃), 1.53 (s, 9H, CO₂C(C₃)₃), 3.92 (q, 2H, J=7.6Hz, CO₂C₂CH₃), 3.97 (s, 3H, ArOC₃), 4.42 (q, 2H, J=7.9Hz, OC₂CF₃), 4.85 (d, 2H, J=17.5Hz, NC₂CO₃), 7.23 (d, 1H, J=9.5Hz, Ar ), 7.38 (d, 1H, J=9.2Hz, Ar ), 8.08 (d, 1H, J=9.5Hz, Ar ), 8.24 (d, 1H, J=8.7Hz, Ar ).

IR (CHCl₃, cm⁻¹): 2995 (CH), 1744 (2C=O), 1678 (C=O), 1604 (C=C).

Analysis: Calculated: C 52.08 H 4.55 N 2.53 %

Found: C 52.02 H 4.24 N 2.54%.

Step 3) Preparation of N-(ethoxycarbonyl)-N-[[6-methoxy-2- (2,2,2-trifluoroethoxy)-5-(trifluoromethyl)-1-naphthalenyl]-carbonyl]-glycine

A suspension of 4.50 g (8.13 mmol) of the 1,1-dimethylethyl ester of N-(ethoxycarbonyl-N[[6-methoxy-2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]glycine in 140 ml of formic acid was stirred at room temperature under a dry nitrogen atmosphere. Dissolution occurred after 10 min. After 1 h, the reaction mixture was diluted with 1.3 l of water and stirred rapidly for 5 min. The resulting oil was extracted twice with 150 ml of ether each time. The extracts were combined and the ether was removed. The residue was suspended in 50 ml of water and filtered. The solid was washed twice with 30 ml of water each time and dried for 30 min. The crude product was then recrystallized from chloroform:petroleum ether, whereby 2.06 g (51%) of the title compound were obtained as white crystals, mp 165.5-167°C.

NMR (d6DMSO, 400 MHz): δ 0.65 (t, 3H, J=7.1Hz, CO₂CH₂C₃), 3.84 (q, 2H, J=7.1Hz, CO₂C₂CH₃), 3.99 (s, 3H, ArOC₃), 4.50 (d, 1H, J=17.0Hz, NC ¹H²CO₂H), 4.65 (d, 1H, J=17.5Hz, NCH¹ ²CO₂H), 4.89 (dq, 2H, J=8.8 and 2.3 Hz, OC₂CF₃), 7.66 (d, 1H, J=9.8Hz, Ar ), 7.67 (d, 1H, J=9.5Hz, Ar ), 8.01 (d, 1H, J=9.5Hz, ArH), 8.12 (dd, 1H, J=9.7 and 1.2Hz, Ar ).

IR (KBr, cm-1): 1749 (C=O), 1731 (C=O), 1677 (C=O), 1602 (C=C).

MS (c/e): 497 (37%), 351 (63%), 86 (100%).

Analysis: Calculated: C 48.30 H 3.44 N 2.82 %

found: C 48.34 H 3.83 N 2.74%.

Example 8: N-[[2-chloro-6-methoxy-5-(trifluoromethyl)-1- naphthalenyl]-carbonyl]-N-(ethoxycarbonyl)-glycine (I): R¹ = -Cl; R² = -CH₂CH₃, X = -OH. Step 1) Preparation of the ethyl ester of N-[[2-chloro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]-carbonyl]-carbamic acid

A solution of 3.50 g (11.5 mmol) of 2-chloro-6-methoxy-5-(trifluoromethyl)-naphthoic acid (prepared by the procedure of Example 14) and 2.2 g (1.1 eq.) of ethoxycarbonyl tert-butylcarbodiimide in 58 mL of dry tetrahydrofuran was heated to reflux under a dry nitrogen atmosphere for 5½ h. The tetrahydrofuran was removed and the resulting solid was triturated with two 15 mL portions of ether and dried in vacuo. A second crop was recovered from the ether and combined with the product (3.36 g, 78%). A small sample was further purified by flash chromatography (70/30 petroleum ether/ethyl acetate) to give the analytically pure product as a white solid, m.p. 169-171 °C.

NMR (CDCl3, 200 MHz): δ 1.18 (t, 3H, J=7Hz, CH₂C₃), 3.99 (s, 3H, OC₃) 4.12 (q, 2H, J=7Hz, C₂CH₃), 7.37 (d, 1H, Ar ), 7.51 (d, 1H, J=10Hz, Ar ), 7.90 (d, 2H, Ar , N ), 8.21 (d, 1H, J=10Hz , Ar ).

IR (CHCl₃, cm⁻¹): 3400 (NH), 1765 (C=O), 1690 (C=O), 1615 and 1585 (C=C).

Analysis: Calculated: C 51.15 H 3.49 N 3.73 %

found: C 51.08 H 3.51 N 3.46%.

Step 2) Preparation of the 1,1-dimethylethyl ester of N-[[2- chloro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]-carbonyl]-N- (ethoxycarbonyl)-glycine

To a solution of 3.20 g (8.52 mmol) of the ethyl ester of N-[[2-chloro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]carbamic acid in 100 ml of dry tetrahydrofuran under a dry nitrogen atmosphere at room temperature was added 0.281 g (1.1 eq.) of sodium hydride (80 wt.% dispersion in mineral oil). After stirring for 1 h, 2.06 ml (1.5 eq.) of tert-butyl bromoacetate were added. The reaction mixture was stirred for 25 min at room temperature, heated to 65°C for 1 h and cooled back to room temperature. The solvent was removed and the residue was dissolved in 200 ml of ether, washed twice with 50 ml of water and once with 50 ml of saturated aqueous NaCl, dried over magnesium sulfate, filtered and combined with silica gel. The ether was removed and the absorbate was flash chromatographed (93/7 petroleum ether/ethyl acetate) to give 3.58 g (86%) of product as a white solid. A small amount was triturated with petroleum ether and dried overnight in vacuo at 40 °C to give the analytical sample, m.p. 107-108 °C.

NMR (CDCl3, 200 MHz): δ 0.77 (t, 3H, J=7Hz, OCH₂C₃), 1.55 (s, 9H, C(C₃)₃), 3.93 (q, 2H, J=6Hz, OC &sub2;CH&sub3;), 3.99 (s, 3H, ArOC &sub3;), 4.51 (d, 1H, J=18Hz, NC ¹H²), 4.84 (d, 1H, J=17Hz, NCH¹ ²) , 7.40 (d, 1H, J=10Hz, Ar ), 7.47 (d, 1H, J=10Hz, Ar ), 8.15 (m, 2H, Ar ).

IR (CHCl₃, cm⁻¹): 1750-1730 (C=O), 1675 (C=O).

Analysis: Calculated: C 53.94 H 4.73 N 2.86 %

found: C 53.57 H 4.52 N 2.83%.

Step 3) Preparation of N-[[2-chloro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]-carbonyl]-N-(ethoxycarbonyl)-glycine

A suspension of 3.13 g (6.39 mmol) of the 1,1-dimethylethyl ester of N-[[2-chloro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]-N-(ethoxycarbonyl)glycine in 120 ml of formic acid was stirred for 3 h at room temperature under a dry nitrogen atmosphere. Dissolution occurred after 1 h. The reaction mixture was diluted with 1.5 L of water and extracted with ether. The extracts were combined, washed well with water and concentrated to leave an oil. The oil was diluted with water and extracted with chloroform. The extracts were combined, dried over magnesium sulfate, filtered and concentrated. The crude solid was recrystallized from benzene:petroleum ether and dried overnight at 90 °C in vacuo to give 2.31 g (85%) of the title compound as a white solid, m.p. 144-146 °C. NMR (CDCl 3 , 400 MHz): ? 0.78 (t, 3H, J=7Hz, -CH2C3), 3.97 (q, 2H, J=7Hz, C2CH3), 4.00 (s, 3HOC3), 4.79 (d, 1H, J=17Hz, NC1H2), 5.00 (d, 1H, J=17Hz, NCH1¹²), 7.39 (d, 1H, J=9Hz, Ar), 7.50 (d, 1H, J=9Hz, Ar), 8.02 (d, 1H, J=9Hz, Ar), 8.20 (d, 1H, J=9Hz, Ar). IR (KBr, cm-1): 3200-2800 (COOH), 1765 (C=O), 1735 (C=O), 1690 (C=C).

MS (Cl): 434 (m+H) (76%), 414 (36%), 309 (80%), 287 (100%), 253 (58%), 187 (54%).

Analysis: Calculated: C 49.84 H 3.48 N 3.23 %

found: C 49.68 H 3.36 N 3.18%.

Example 9: N-[[2-Bromo-6-methoxy-5-(trifluoromethyl)-1- naphthalenyl]-carbonyl]-N-(ethoxycarbonyl)-glycine (I): R¹ = -Br; R² = -CH₂CH₃, X = -OH. Step 1) Preparation of 2-bromo-N-(ethoxycarbonyl)-6-methoxy- 5-(trifluoromethyl)-1-naphthalenecarboxamide

According to the procedure of O. Mitsunobu et al., Bull.Chem.Soc., Japan, 45, 3607 (1972), a solution of 4.50 g (12.9 mmol) of 2-bromo-6-methoxy-5-trifluoromethyl-1-naphthoic acid (prepared by the procedure of Step 2, Example 11) and 2.40 g (14.1 mmol) of ethoxycarbonyl tert-butylcarbodiimide in 80 ml of dry tetrahydrofuran was refluxed under a dry nitrogen atmosphere for 2 1/3 h. The THF was removed, the residue dissolved in chloroform and the solvent evaporated. The resulting solid was triturated with ether (2 x 5 mL) and dried in vacuo to give 4.61 g (85%) of the title compound as an off-white solid, m.p. 169-171°C. NMR (CDCl3, 200 MHz): δ 1.18 (t, 3H, J=6.9Hz, CO₂CH₂C ₃), 3.99 (s, 3H, ArOC ₃) 4.12 (q, 2H, J=6.9Hz, CO₂C ₂CH₃), 7.35 (d, 1H, J=9.1Hz, Ar ), 7.65 (d, 1H, J=9.5Hz, Ar ), 7.87 (s, 1H, N ), 7.90 (d, 1H, J=9.6Hz, Ar ), 8.13 (d, 1H, J=9.6Hz, Ar ).

IR (CHCl₃, cm⁻¹): 3400 (NH), 1765 (C=O), 1692 (C=O), 1616 and 1582 (C=C).

Analysis: Calculated: C 45.73 H 3.12 N 3.33 %

found: C 45.68 H 3.50 N 3.21 %.

Step 2) Preparation of the 1,1-dimethylethyl ester of N-[[2- bromo-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]-carbonyl]-N- (ethoxycarbonyl)-glycine

To a stirred solution of 4.41 g (10.5 mmol) of 2-bromo-N-(ethoxycarbonyl)-6-methoxy-5-(trifluoromethyl)-1-naphthalenecarboxamide in 150 ml of anhydrous tetrahydrofuran at room temperature under a dry nitrogen atmosphere was added 0.347 g (1.1 eq.) sodium hydride (80 wt.% dispersion in mineral oil) was added. After 1 h, 2.54 mL (1.5 eq.) tert-butyl bromoacetate was added and the reaction mixture was heated to 55 °C. After 1 1/2 h of heating, the reaction mixture was cooled to room temperature and the THF was removed. The residue was suspended in 250 mL of ether, washed twice with 100 mL of water and once with 50 mL of saturated aqueous NaCl, dried with magnesium sulfate and the ether was removed. The resulting oil was triturated once with 50 mL of petroleum ether to give 4.78 g (85%) of the title compound as a white powder. A small sample was recrystallized from ether-petroleum ether to give white crystals for analysis, m.p. 109.5-112 °C.

NMR (CDCl3, 200 MHz): δ 0.75 (t, 3H, J=6.8Hz, CO₂CH₂C₃), 1.54 (s, 9H, CO₂C(C₃)₃), 3.91 (q, 2H, J=7.0Hz, CO₂C₂CH₃), 3.98 (s, 3H, ArOC₃), 4.50 (d, 1H, J=17.2Hz, NC ¹H²CO₂), 4.83 (d, 1H, J=16.6Hz, NCH¹ ²CO₂), 7.38 (d, 1H, J=9.2Hz, Ar ), 7.60 (d, 1H, J=9.6Hz, Ar ), 8.11 (dd, 2H, J=11.0 and 9.8Hz, Ar ).

IR (CHCl₃, cm⁻¹): 2975 (CH), 1732 (C=O), 1672 (C=O), 1610 and 1578 (C=C).

Analysis: Calculated: C 49.45 H 4.34 N 2.62 %

Found: C 49.69 H 4.36 N 2.75%.

Step 3) Preparation of N-[[2-bromo-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]-carbonyl]-N-(ethoxycarbonyl)-glycine

A suspension of 4.68 g (8.76 mmol) of the 1,1-dimethylethyl ester of N-[[2-bromo-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]-N-(ethoxycarbonyl)glycine in 150 ml of formic acid was stirred at room temperature under a dry nitrogen atmosphere. Dissolution occurred after 15 min. After 1 ¼ h, the reaction mixture was diluted with 1.2 l of water. The aqueous phase was extracted twice with 300 ml of ether each time. The extracts were combined, dried with magnesium sulfate and the ether was removed. The residue was suspended in 150 ml of water and filtered. The solid was washed twice with 30 ml of water each time and dried. The crude product was recrystallized twice from chloroform:hexane to give 2.24 g (53%) of the title compound as white needles, mp 167-168.5 °C.

NMR (d6DMSO, 400 MHz): δ 0.69 (t, 3H, J=7.1Hz, CO₂CH₂C ₃), 3.87 (t, 2H, J=7.1Hz, CO₂C ₂CH₃), 4.02 ( s, 3H, ArOC&sub3;), 4.59 (d, 1H, J=19.9Hz, NC ¹H²CO₂H), 4.71 (d, 1H, J=17.4Hz, NCH¹ ²CO₂H), 7.71 (d, 1H, J=9.5Hz, Ar ), 7 ,82 (d, 1H, J=9.4Hz, Ar ), 8.01 (d, 1H, J=9.3Hz, Ar ), 8.15 (d, 1H, J=9.5 Ar ).

IR (KBr, cm-1): 1761 (C=O), 1738 (C=O), 1690 (C=0), 1620 and 1589 (C=C).

MS (c/e): 479 (2.4%), 477 (2.6%), 398 (46%), 352 (20%), 333 (25%), 331 (25%), 324 (100%), 269 (51%).

Analysis: Calculated: C 45.21 H 3.16 N 2.93 %

Found: C 45.36 H 2.89 N 2.87%.

Example 10 : 2-Fluoro-6-methoxy-5-(trifluoromethyl)-1- naphthoic acid (II): R¹ = -F Step 1) Preparation of 1-bromomethyl-2-fluoro-6-methoxy-5- (trifluoromethyl)-naphthalene

A suspension of 6.93 g (1.1 eq.) of N-bromosuccinimide, 38 mg of benzoyl peroxide and 9.14 g (35.39 mmol) of 2-fluoro-6-methoxy- 1-methyl-5-(trifluoromethyl)-naphthalene in 160 ml of carbon tetrachloride was refluxed with stirring under a dry nitrogen atmosphere for 1 1/2 h. The reaction mixture was cooled to room temperature and filtered. The solid was washed three times with 30 ml of carbon tetrachloride each time. The solvent was removed from the combined CCl₄ phases to give the product as a white solid in quantitative yield. A small amount of this solid was recrystallized from hexane:ethyl acetate, m.p. 97-100 °C.

NMR (CDCl3, 200 MHz): δ 4.01 (s, 3H, OC₃), 4.94 (d, 2H, J=1.5Hz, C₂Br), 7.32 (t, 1H, J=9.4Hz, ArH), 7.49 (d, 1H, J=9.5Hz, Ar ), 8.25 (m, 1H, Ar ), 8.25 (d, 1H, Ar ).

IR (CHCl₃, cm⁻¹): 1615 (aromatic C-C).

Analysis: Calculated: C 46.32 H 2.69 %

found: C 46.04 H 2.34%.

Step 2) Preparation of 2-fluoro-1-hydroxymethyl-6-methoxy-5- (trifluoromethyl)-naphthalene

A suspension of 11.16 g (35 mmol) 1-bromomethyl-2-fluoro-6-methoxy-5-(trifluoromethyl)-naphthalene, 5.85 g (86 mmol) sodium formate, 134 ml ethanol and 34 ml water was heated to reflux with stirring. Dissolution occurred within 20 min. After 1 ½ h the heat source was removed, 14 mL of 2.5 N NaOH was added and the reaction mixture was cooled to room temperature. The ethanol was removed, 100 mL of water was added and the solid was filtered. The white solid was washed with water and dried in vacuo to give the product in quantitative yield. A small amount was recrystallized from petroleum ether:ethyl acetate, m.p. 113-114 °C.

NMR (CDCl3, 200 MHz): δ 1.74 (t, 1H, J=6.2Hz, -O ), 3.99 (s, 3H, OC 3 ), 5.15 (dd, 2H, J=1.3 and 6.2Hz, - C 2 OH), 7.32 (t, 1H, J=9.4Hz, Ar ), 7.42 (d, 1H, J=9.4Hz, Ar ), 8.18 (m, 1H, Ar ) , 8.41 (d, 1H, J=9.4Hz, ArH).

IR (CHCl₃, cm⁻¹): 3610, 3420 (OH), 1615 (aromatic C-C).

Analysis: Calculated: C 56.94 H 3.67 %

found: C 56.71 H 3.86%.

Step 3) Preparation of 2-fluoro-6-methoxy-5-(trifluoromethyl)- 1-naphthoic acid

25 mL (66.8 mmol) of Jones reagent (2.67 M in CrO3) was added dropwise over 5 min to a mechanically stirred cold (0-10°C) solution of 11.59 g (34.6 mmol) of 2-fluoro-1-hydroxymethyl-6-methoxy-5-(trifluoromethyl)-naphthalene in 120 mL of acetone. The reaction mixture was warmed to room temperature and after 2 h quenched with isopropanol. The reaction mixture was diluted with ether to a volume of approximately 500 mL and then filtered through diatomaceous earth. The diatomaceous earth was washed with more ether. The ether was removed and the residue dissolved in 100 mL of 5% NaOH. An additional 100 mL of water was added and this aqueous phase was extracted four times with 200 mL of ether, once with 100 mL of ethyl acetate and once with 200 mL of CH2Cl2. These extracts were discarded. The basic phase was acidified to pH 1-3 with 10% HCl and the tan solid was collected and dried in vacuo (7.3 g, 73%). A small sample was recrystallized from ethanol:water, m.p. 179-181 °C.

NMR (CDCl3, 200 MHz): δ 4.02 (s, 3H, OC₃), 7.40 (t, 1H, J=9.5Hz, Ar ), 7.46 (d, 1H, J=9.6Hz, Ar ), 8.37 (m, 1H, Ar ), 8.53 (d, J=9.6Hz, ArH).

IR (KBr, cm⁻¹): 3600-2500 (CO₂H), 1695 (CO₂H).

Exact mass: Calculated 288.0409; found = 288.0380.

Example 11 : 6-Methoxy-2-(2,2,2-trifluoroethoxy)-5- (trifluoromethyl)-naphthoic acid (II): R¹ = -O-CH₂-CF₃. Step 1) Preparation of (2-bromo-6-methoxy-5-trifluoromethyl-1- naphthalenyl)-methanol

Following the procedure of E.L. Eliel et al., J.Chem.Soc., 1628 (1955), 12.88 g (2.4 eq.) of sodium formate and 42 mL of water were added to a stirred suspension of 32.4 g (78.0 mmol) of 2-bromo-1-bromomethyl-6-methoxy-5-trifluoromethylnaphthalene (prepared by the procedure of Example 13) in 160 mL of ethanol at room temperature. The suspension was heated to reflux and after 1 h an additional 1.07 g (0.2 eq.) of sodium formate was added. After 10 3/4 h, 25 mL of water was added and the ethanol was distilled off. The reaction mixture was cooled to room temperature and basified to pH 9 with 10% aqueous sodium hydroxide solution. The basic suspension was diluted with 1.5 L of water and filtered. The solid was washed with 30 mL of water twice and then triturated with 25 mL of chloroform twice and dried to give 23.10 g (87%) of a light yellow solid. A small sample was flash chromatographed (7:3 to 3:2 petroleum ether:ethyl acetate gradient elution, silica) to give a white solid for analysis, mp 171-173 °C.

NMR (d6DMSO, 200 MHz): δ 4.01 (s, 3H, ArOC₃), 5.07 (d, 2H, J=4.4Hz, C₂OH), 5.44 (t, 1H, J=5.2Hz, CH₂O ), 7.70 (d, 1H, J=9.5Hz, Ar ), 7.78 (d, 1H, J=9.1Hz, Ar ), 7.90 (d, 1H, J=9.9Hz, Ar ), 8.56 (d, 1H, J=10.2 Ar ).

IR (KBr, cm-1): 3318 (OH), 1613 and 1588 (C=C).

Analysis: Calculated: C 46.59 H 3.01 %

found: C 46.77 H 3.36%.

Step 2) Preparation of 2-bromo-6-methoxy-5-trifluoromethyl-1-naphthoic acid

34 mL (1.32 eq.) of Jones reagent (2.67 M in CrO₃) was slowly added to a stirred solution of 23.10 g (68.9 mmol) of (2-bromo-6-methoxy-5-trifluoromethyl-1-naphthalenyl)-methanol in 450 mL of acetone at 0 °C. After 5 min, the reaction mixture was warmed to room temperature. After 1 h, an additional 6.8 mL (0.26 eq.) of Jones reagent was added. After 2 ½ h, the reaction mixture was quenched with 10 ml of isopropanol and diluted with 1.4 L of water. The aqueous phase was extracted three times with 400 ml of ethyl acetate each. The extracts were combined and the ethyl acetate phase was extracted quickly three times with 350 ml of 5 N sodium hydroxide solution each. The basic extracts were combined and acidified to pH 1 with concentrated hydrochloric acid. The aqueous acid suspension was stirred overnight at room temperature. The solid was collected by suction filtration, washed once with 25 ml of water and dried to give 16.05 g (67%) of a light yellow solid, m.p. 221-222.5 °C.

NMR (d6DMSO, 400 MHz): δ 4.02 (s, 3H, ArOC₃), 7.77 (d, 1H, J=9.7Hz, Ar ), 7.84 (d, 1H, J=9.4Hz, Ar ), 8.02 (d, 2H, J=9.3Hz, ArH).

IR (KBr, cm-1): 1710 (C=O), 1612 and 1583 (C=C).

MS (c/e): 350 (99%), 348 (100%), 333 (20%), 331 (20%), 307 (24%), 305 (26%).

Analysis: Calculated: C 44.73 H 2.31 %

found: C 44.69 H 2.38 %.

Step 3) Preparation of 6-methoxy-2-(2,2,2-trifluoroethoxy)-5- (trifluoromethyl)-naphthoic acid

To a suspension of 7.68 g (6.7 eq.) of sodium hydride (60 wt.% dispersion in mineral oil) in 85 mL of anhydrous hexamethylphosphoramide at room temperature, contained in a flame-dried reaction vessel under argon, was slowly added 8.35 mL (4.0 eq.) of 2,2,2-trifluoroethanol. After 20 min, 10.00 g (28.6 mmol) of 2-bromo-6-methoxy-5-trifluoromethyl-1-naphthoic acid and 10.91 g (2.0 eq.) of copper(I) iodide were carefully added. After 50 min, the reaction mixture was heated to 65°C for 1 1/2 h and then cooled to room temperature. The reaction mixture was diluted with 800 mL of water and acidified to pH 1 with concentrated hydrochloric acid. The acid phase and 200 ml of ethyl acetate are stirred together for 15 minutes and then filtered through diatomaceous earth; the diatomaceous earth was washed twice with 100 ml of ethyl acetate each time. The two layers of the filtrate were separated. The aqueous layer was extracted twice with 150 ml of ethyl acetate each time. All ethyl acetate phases were combined and the ethyl acetate was removed. The residue was dissolved in 800 ml of 0.5 N sodium hydroxide and washed twice with 150 ml of ether. The extracts were discarded. The basic phase was acidified to pH 1 with concentrated hydrochloric acid. The acidic phase was extracted three times with 200 mL of ether each time. The extracts were combined, washed once with 50 mL of saturated aqueous sodium chloride, dried with magnesium sulfate and the ether was removed to give 9.33 g (88%) of a light yellow solid. A small sample was recrystallized from ethanol:water for analysis, m.p. 190-192 °C. NMR (d6 DMSO, 200 MHz): δ 3.99 (s, 3H, ArOC₃), 4.93 (q, 2H, J=8.9Hz, OC₂CF₃), 7.71 (2d, 2H, J=4.4 and J=9.4Hz, Ar), 8.00 (d, 1H, J=9.5Hz, Ar), 8.13 (d, 1H, J=8.4Hz, Ar).

IR (KBr, cm-1): 1718 (C=O), 1614 (C=C).

Analysis: Calculated: C 48.93 H 2.74 %

found: C 48.90 H 3.13%.

Example 12: Step 1) Preparation of 1-bromomethyl-2-chloro-6-methoxy-5-trifluoromethylnaphthalene

To a stirred solution of 16.3 g (0.0593 mol) of 2-chloro-6- methoxy-1-methyl-5-trifluoromethylnaphthalene (prepared by the procedure of Example 14, Step 2) in 200 mL of carbon tetrachloride at room temperature under a dry nitrogen atmosphere were added 11.62 g (1.1 eq) of N-bromosuccinimide and 0.061 g (0.0044 eq) of benzoyl peroxide. The reaction mixture was refluxed with an additional 10.55 g (1 eq) of N-bromosuccinimide for 29 h and after 5 1/2 h 0.035 g (0.0025 eq) of benzoyl peroxide was added. The reaction mixture was cooled to room temperature and filtered. The solid was washed with hot carbon tetrachloride. The filtrate was concentrated to give 21.88 g (100%) of a white solid product. A small sample was purified by flash chromatography (4/1 petroleum ether/chloroform) to give an analytical sample, mp 127-130 °C.

NMR (CDCl3, 200 MHz): δ 4.01 (s, 3H, OC₃), 5.05 (s, 2H, C₂Br), 7.46 (d, 1H, J=8Hz, Ar ), 7.50 (d, 1H, J=7Hz, Ar ), 8.13 (d, 1H, J=8Hz, Ar ), 8.26 (d, 1H, J=10Hz, ArH).

IR (CHCl₃, cm⁻¹): 1610 and 1580 (C=C).

Analysis: Calculated: C 44.16 H 2.56 %

found: C 44.13 H 2.46 %.

Step 2) Preparation of 2-chloro-1-hydroxymethyl-6-methoxy-5-trifluoromethylnaphthalene

To a stirred suspension of 20.97 g (0.0593 mol) of 1-bromomethyl-2-chloro-6-methoxy-5-trifluoromethylnaphthalene in 226 mL of ethanol at room temperature was added 9.68 g (2.4 eq.) of sodium formate and 57 mL of water. The reaction mixture was heated at reflux for 3½ h. The heat source was removed and 27 mL (1 eq.) of 2.5 N sodium hydroxide was added to the stirred hot mixture. The ethanol was removed and the residue was diluted with about 100 mL of water. The aqueous suspension was filtered. The solid was washed with water and dried in vacuo to give 16.01 g (93%) of an off-white solid product. A small sample was purified by flash chromatography (3/2 petroleum ether:ethyl acetate) to give an analytical sample, m.p. 162-166ºC.

NMR (CDCl3, 200 MHz): δ 1.86 (t, 1H, J=5Hz, -CH₂OH), 4.04 (s, 3H, OC₃), 5.29 (d, 2H, J=5Hz, C₂OH), 7 ,44 (d, 1H, J=10Hz, Ar ), 7,53 (d, 1H, J=10Hz, Ar ), 8,16 (d, J=10Hz, Ar ), 8,46 (d, 1H, J=10Hz, Ar ).

IR (KBr cm-1): 3290 (-OH), 1608 (C=C).

Analysis: Calculated: C 53.90 H 3.13 %

found: C 53.81 H 3.36%.

Step 3) Preparation of 2-chloro-6-methoxy-5-(trifluoromethyl)- naphthoic acid

27 mL (1.34 eq) of Jones reagent (2.67 M in CrO3) was added to a mechanically stirred solution of 15.61 g (0.0537 mol) of 2-chloro-1-hydroxymethyl-6-methoxy-5-trifluoromethylnaphthalene in 324 mL of acetone at 0 °C. The reaction mixture was warmed to room temperature and stirred for 4 h with an additional 10 mL (0.50 eq) of Jones reagent added after 2 h. The reaction mixture was quenched with about 250 mL of isopropanol, diluted with about 1 L of ether, and filtered through diatomaceous earth. The filtrate was concentrated and the residue dissolved in 150 mL of 5% NaOH. The aqueous phase was extracted with 1 L of ether and 500 mL of methylene chloride. The extracts were discarded. The aqueous phase was acidified with 10% hydrochloric acid to pH 1. The solid precipitate was filtered, washed with water and dried in vacuo at 80ºC to give 10.98 g (67%) of product as white solid. A small amount was recrystallized from chloroform/petroleum ether to give the analytical sample, m.p. 214ºC (dec.).

NMR (d6DMSO, 200 MHz): δ 4.02 (s, 3H, OC 3 ), 7.75 (t, 2H, J=10Hz, Ar ), 8.03 (d, 1H, J=10Hz, Ar ), 8.11 (d, 1H , J=10Hz, Ar).

IR (KBr, cm-1): 3600-2500 (CO-2H), 1687 (C=O).

Analysis: Calculated: C 51.25 H 2.65 %

found: C 50.89 H 2.84%.

Example 13 : Preparation of 2-bromo-1-bromomethyl-6- methoxy-5-trifluoromethylnaphthalene

To a stirred solution of 25.19 g (78.9 mmol) of 2-bromo-6-methoxy-1-methyl-5-trifluoromethylnaphthalene (prepared by the procedure of Example 14, Step 1) in 300 mL of carbon tetrachloride at room temperature under a dry nitrogen atmosphere were added 21.07 g (1.5 eq) of N-bromosuccinimide and 84 mg (0.0044 eq) of benzoyl peroxide. The reaction mixture was heated to reflux for 6 h and then cooled to approximately 50 °C. The warm reaction mixture was filtered. The solid was washed twice with 30 mL of warm carbon tetrachloride each time. The carbon tetrachloride was removed from the filtrate to give 32.4 g (100%) of a light yellow solid. Mp. 141.5-143ºC.

NMR (CDCl3, 200 MHz): δ 4.02 (s, 3H, OC₃), 5.09 (s, 2H, C₂Br), 7.46 (d, 1H, J=9.5Hz, Ar ), 7.66 (d, 1H, J=9.5Hz, ArH), 8.06 (dm, 1H, Ar ), 8.30 (d, 1H, J=9.5Hz, Ar ).

IR (CHCl₃, cm⁻¹): 1615, 1585 (ArC-C).

Analysis: Calculated: C 39.23 H 2.28 %

found: C 39.90 H 2.41 %.

Example 14: Step 1) Preparation of 2-bromo-6-methoxy-1-methyl-5-trifluoromethylnaphthalene

A solution of 6.41 mL (0.125 mol) of bromine in 28 mL of glacial acetic acid was added over a period of 25 min to a stirred solution of 20.9 g (0.083 mmol) of 2-methoxy-5-methyl-1-trifluoromethylnaphthalene in 300 mL of glacial acetic acid. The solution was stirred for 22 h at room temperature. The reaction mixture was poured into 2 L of dilute aqueous NaHSO3. The yellow solid product was collected by suction filtration and dried in vacuo (26.2 g, 98%), m.p. 98-100.5 °C.

NMR (CDCl3, 200 MHz): δ 2.77 (s, 3H, OC 3 ), 3.99 (s, 3H, OC 3 ), 7.33 (d, 1H, J=9.5Hz, Ar ), 7.63 (d, 1H , J=9.6Hz, Ar ), 7.91 (dm, 1H, Ar ), 8.19 (d, 1H, J=9.5Hz, Ar ).

IR (CHCl₃, cm⁻¹): 1610 (ArC-C).

Analysis: Calculated: C 48.93 H 3.16 %

found: C 48.57 H 3.38%.

Step 2) Preparation of 2-chloro-6-methoxy-1-methyl-5-trifluoromethylnaphthalene

35.78 g (6 eq.) of cuprous chloride was added to a solution of 19.22 g (0.0602 mol) of 2-bromo-6-methoxy-1-methyl-5-trifluoromethylnaphthalene in 194 mL of dry DMSO at room temperature under a nitrogen atmosphere. The reaction mixture was heated to about 188°C for 3 h, then cooled to room temperature and diluted with 3 L of water. The resulting solids were collected and triturated well with a total of 2 L of ethyl acetate. The triturated material was combined, dried over magnesium sulfate, filtered and the solvent removed to give 16.7 g (100%) of the desired product as a white solid. A small sample was purified by flash chromatography (eluent 90/10 petroleum ether/chloroform) to give an analytically pure product, m.p. 102-103 °C.

NMR (CDCl3, 200 MHz): δ 2.72 (s, 3H, -C₃), 3.99 (s, 3H, OC₃), 7.34 (d, 1H, J=10Hz, Ar ), 7.48 (d, 1H, J=10Hz, Ar ), 7.98 (d, 1H, J=9Hz, Ar ), 8.17 (d, 1H, J=10Hz, Ar ).

IR (CHCl₃, cm⁻¹): 2950 and 2858 (CH), 1610 and 1590 (C=C).

Analysis: Calculated: C 56.85 H 3.67 %

found: C 56.57 H 3.95%.

Example 15 : 2-Fluoro-6-methoxy-1-methyl-5-(trifluoromethyl)-naphthalene Step 1) Preparation of 2-methoxy-5-methyl-6-nitro-1-(trifluoromethyl)-naphthalene

To a solution of 640 ml of acetic anhydride cooled to 3 to 4ºC, 160 ml of fuming nitric acid (90%, specific gravity 1.5) were added dropwise using an additional funnel at a rate such that the internal temperature was maintained at or below 8°C (about 1 hour and 20 minutes total addition time). After the internal temperature was cooled back to 3-4°C, 200 g (0.833 moles) of 2-methoxy-5-methyl-1-trifluoromethylnaphthalene was added in portions. The portions added were small enough that the internal temperature did not rise above 10°C and each portion was added when the temperature had dropped to 5°C (addition time about 1 1/4 hours). After an additional 15 minutes, the reaction mixture was added to 3 L of water. The resulting amorphous solid was filtered and washed with water and the clumps were broken up and dried in vacuo overnight. The dry solid (about 225 g) was recrystallized from 3 L of 95:5 ethanol:isopropanol. The resulting long yellow needles were filtered and washed twice with 50 ml of ethanol each to give 97.5 g (41%) of product, mp 141-142 °C.

NMR (CDCl3, 200 MHz): δ 2.84 (s, 3H, -C₃), 4.05 (s, 3H, OC₃), 7.47 (d, 1H, J=10.0Hz, Ar ), 7.87 (d, 1H, J=9.9Hz, Ar ), 8.16 (dm, 1H, Ar ), 8.39 (d, 1H, J=10.0Hz, ArH).

IR (CHCl₃, cm⁻¹): 1615 (aromatic C=C).

MS (c/e): 285 (67%), 268 (80%), 266 (13%), 248 (48%), 240 (42%), 196 (100%), 146 (100%).

Analysis: Calculated: C 60.47 H 3.90 %

found: C 60.28 H 3.80 %.

Step 2) Preparation of 6-amino-2-methoxy-5-methyl-1-trifluoromethylnaphthalene

A suspension of 16.5 g (57.85 mmol) of 2-methoxy-5-methyl- 6-nitro-1-trifluoromethylnaphthalene and 1.69 g of 10% palladium on carbon in 900 mL of absolute ethanol was hydrogenated at 40 psi H2 pressure for 2 h at room temperature. The reaction mixture was then filtered through sulkafloc and the sulkafloc was washed with fresh ethanol. The ethanol was then removed from the filtrate to give 14.3 g (97%) of product as a yellow solid, mp 109-110 °C.

NMR (CDCl3, 200 MHz): δ 2.40 (s, 3H, C₃), 3.77 (broad s, 2H, N₂), 3.95 (s, 3H OC₃), 7.04 (d, 1H, J=9 ,7Hz, Ar ), 7.26 (d, 1H, J=9.5Hz, Ar ), 7.92 (dm, 1H, Ar ), 8.05 (d, 1H, J=9.5Hz, ArH) .

IR (CHCl₃, cm⁻¹): 3510, 3420 (NH₂), 1630, 1610 (aromatic (C-C).

MS (c/e): 255 (100%), 234 (79%), 212 (75%).

Analysis: Calculated: C 61.17 H 4.74 N 5.49 %

found: C 61.38 H 4.40 N 5.40 %.

Step 3) Preparation of 2-fluoro-6-methoxy-1-methyl-5- (trifluoromethyl)-naphthalene

A 250 mL Nalgene bottle with magnetic stir bar under N2 atmosphere was charged with 75 mL of HF-pyridine (70 to 30 wt%) and cooled to -78°C in a dry ice-isopropanol bath. When the HF-pyridine solution was frozen, a solution of 10.07 g (39.4 mmol) of 6-amino-2-methoxy-5-methyl-1-trifluoromethylnaphthalene in 25 mL of pyridine (previously dried over KOH) was slowly added. When the solution was frozen, 4.55 g (1.67 eq) of solid sodium nitrite was again added and the dry ice-isopropanol bath was removed. The reaction mixture was stirred at room temperature for 30 min (after 10 min the frozen solids had melted). The reaction mixture was then heated in an oil bath at 65°C for 2 h. During this heating period a foamy precipitate had collected in the reaction vessel. The reaction mixture was cooled to room temperature and 1 L of water was added. The aqueous phase was extracted three times with 300 mL of ether each time. The combined ether extracts were washed with 200 mL of saturated aqueous NaCl. 40 mL of silica gel was added to the ether phase and the ether was removed. The silica absorbate was flash chromatographed (95:5 petroleum ether:ethyl acetate) to give 7.82 g (77%) of a white solid product, mp 97-99°C.

NMR (CDCl3, 200 MHz): δ 2.56 (d, 3H, J=2.2Hz, C 3 ), 3.99 (s, 3H, OC 3 ), 7.28 (d, 1H, J=9.3Hz, Ar ), 7 ,34 (t, 1H, J=9.3Hz, Ar ), 8.04 (m, 1H, Ar ), 8.13 (d, 1H, J=9.3Hz, Ar ).

IR (CHCl₃, cm⁻¹): 1615 (aromatic C-C).

MS (c/e): 258 (96%).

Analysis: Calculated: C 60.47 H 3.98 %

found: C 60.28 H 3.81 %.

Claims (9)

1. Compound of formula (I) wherein R¹ is fluorine, chlorine, bromine or trifluoroethoxy; R² is lower alkyl having 1 to 3 carbon atoms and X is -OH or -NH₂, or a pharmaceutically acceptable salt thereof, wherein X is -OH. 2. A compound according to claim 1, wherein R¹ is fluoro, chloro or bromo, R² is methyl or ethyl and X is -OH or -NH₂, or a pharmaceutically acceptable salt thereof, wherein X is -OH. 3. A compound according to claim 1, which N-[[2-fluoro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]- carbonyl]-N-(methoxycarbonyl)-glycine or a pharmaceutically acceptable salt thereof; [[[2-Fluoro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]- carbonyl]-(methoxycarbonyl)-amino]-acetamide; N-(ethoxycarbonyl)-N-[[2-fluoro-6-methoxy-5-(trifluoromethyl)- 1-naphthalenyl]-carbonyl]-glycine or a pharmaceutically acceptable salt thereof; N-[[2-chloro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]- carbonyl]-N-(methoxycarbonyl)-glycine or a pharmaceutically acceptable salt thereof or N-[[2-bromo-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]- carbonyl]-N-(methoxycarbonyl)-glycine or a pharmaceutically acceptable salt thereof. 4. Compound of formula (VI) wherein R¹ is halogen or trifluoroethoxy; R² is lower alkyl having 1 to 3 carbon atoms and R³ is tert.butyl or benzyl. 5. A process for preparing a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof, wherein X is OH, which comprises: (a) the selective removal of the protecting group R³ from a compound of the formula wherein R and R² are as defined in claim 1 and R³ is tert-butyl or benzyl, to give a compound of formula (I) where X is OH; or (b) reacting a compound of formula (I) as defined in claim 1, wherein X is OH, with ammonia to give a compound of formula (I) wherein X is NH₂; or (c) converting a compound of formula (I) wherein X is OH into a pharmaceutically acceptable salt thereof by reaction with a base or converting a pharmaceutically acceptable acceptable salt of a compound of formula (I) into the acid of formula (I) by acid formation. 6. Process for preparing a compound of formula (I) wherein R¹ is halogen, R² is lower alkyl having 1 to 3 carbon atoms, X is -OH or -NH₂, or a pharmaceutically acceptable salt thereof, wherein X is -OH, which comprises: (a) oxidizing the compound of formula (IX) wherein R¹ is as defined above, to form the compound of formula (II) where R¹ is as defined above, (b) reacting the compound of formula (II) with a glycine ester of formula H₂N-CH₂-COOR³ where R³ is tert.butyl or benzyl, to form the compound of formula (III) where R¹ and R³ are as defined above, (c) acylating the compound of formula (III) with an alkyl chloroformate in the presence of a strong base to form the compound of formula (VI) where R¹, R² and R³ are as defined above, (d) selectively removing the protecting group R³ to form compounds of formula (I) wherein R¹ and R² are as defined above and X is -OH, and (e) reacting the compound of formula (I) wherein X is -OH with ammonia to form the compound of formula (I) wherein R¹ and R² are as defined above and X is -NH₂. 7. A process according to claim 6, in which the compound of formula (II) in which R² is bromine is reacted with a metal 2,2,2-trifluoroethoxide in the presence of copper (I) halide to give the compound of formula (II) in which R¹ is 2,2,2-trifluoroethoxy. 8. Process for the preparation of intermediates of formula (VII) wherein R¹ is -F, which involves reacting the compound of formula (XII) a) with sodium nitrite in the presence of hydrogen fluoride-pyridine or b) with sodium nitrite in the presence of tetrafluoroboric acid to form the corresponding diazonium tetrafluoroborate of formula (VII) wherein R¹ is N₂ BF₄, and pyrolyzing the diazonium tetrafluoroborate. 9. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 3 and a pharmaceutically acceptable carrier.